3. Ethics in genetic research and practice

3.3 Genetic screening and testing
Essentially, the screening process may be divided into three phases - the preparation of the participant or patient; the analysis of the genetic material; the interpretation of the analysis coupled with ensuing support programmes.²⁵ It is useful to distinguish between these three phases in a discussion of the ethics of genetic screening and testing. During the preparatory phase, ethical considerations revolving around informed consent must be addressed. The analysis phase raises familiar issues such as adequacy of procedure and confidentiality with respect to the participant or patient. The final phase raises ethical concerns relating to the management of genetic disorders and the subsequent impact of the screening process on the individual and his or her family.²⁵

Genetic screening should be distinguished from genetic testing at the outset. The terms are often used interchangeably, although they represent two different forms of genetic practice. Genetic screening is carried out on groups of people, which could consist of a section of the population defined by age, sex, or other risk factor, or a subgroup within the population, or within broad groups in which genetic factors may be responsible for certain disabilities.²⁶ Genetic screening may be defined as:

"... a search in a 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."²⁶

Genetic testing, on the other hand, leads to a definitive diagnosis in individuals, and is defined to be:

"... the analysis of a specific gene, its product or function, or other DNA and chromosome analysis, to detect or exclude an alteration likely to be associated with a genetic disorder."²⁵

Individuals may desire testing where there is a family history of a specific disease, if they exhibit symptoms of a genetic disorder; or if they are concerned about passing on genetic disorders to their children.²⁷ In addition, genetic testing in individuals is used as a 'fingerprint' in forensics. The areas of focus for genetic testing at present are thus carrier and susceptibility testing, prenatal diagnosis, newborn testing, and forensic testing.²⁸

Screening programmes play a useful part in public health care systems in identifying potentially serious risks that can be prevented by timely treatment.i Testing allows couples the possibility of making informed choices about parenthood and, possibly, in identifying genetic susceptibility to common serious diseases.²⁶ Three goals have been identified for genetic screening:²⁶

1. to contribute to improving the health of persons who suffer from genetic disorders;
2. to allow carriers for a given abnormal gene to make informed choices regarding reproduction; and
3. to move towards alleviating the anxieties of families and communities faced with the prospect of serious genetic disease.

A fourth goal could be added to this list - the reduction of public health costs. Genetic screening is an attractive option for those institutions seeking to manage their public health exposure. It is feared that the greater our ability to predict the costs of heritable diseases, the greater the public pressures on adults not to pass on genes that are associated with particularly bad outcomes.²⁹ Pressure may also be brought to bear on individuals to be tested for genetic predispositions and to act "to save society long- term costs resulting in a new eugenics based, not on undesirable characteristics, but rather on cost-saving."²⁸

However, some consider any aspirations to a 'healthy public' to be misguided because genetic control of the human population, or any form of 'genome cleansing' could easily slide into eugenics.30 Others hold the view that genetic screening at embryo level will take place in developed countries, and if this is not done in developing countries the discrepancy between the two will widen even further.

3.3.1 Scientific basis
Inheritance is determined by the genes, of which there are an estimated 32 000 in the human genome. Genes are large molecules made up of a substance, DNA, whose double helical structure allows both copying and division. The particular sequence of individual chemical sub-units in a gene serves as a molecular code to specify the manufacture of a particular protein. An alteration (mutation) at even a single position of the DNA sequence may cause serious malfunction of the resulting protein. Modern advances in genetics are due to the ability to study DNA directly. At present we have, at best, information on only one-third of the genes.

The genes are arranged in a fixed order on the chromosomes. Chromosomes are elongated strings of DNA and protein that occur in the nucleus of every cell in the body. Unlike genes, chromosomes can be seen through a light microscope, especially when they become compacted during cell division. In the normal human there are two sets of 23 chromosomes, 46 in all, one set having been inherited from the father, the other from the mother. The members of 22 of the 23 pairs appear identical: these are the autosomes. The remaining pair, the sex chromosomes, differ between males and females; females have a pair of X chromosomes whereas a male has one X chromosome (inherited from his mother) and one Y chromosome (inherited from his father).

Medical genetics is part of the human genetics concerned with the role of genes in illness. Traditionally, the analysis of the genetic contribution to illness and human characteristics has been divided into:

1. disorders due to changes in single genes;
2. disorders influenced by more than one gene (polygenic); and
3. chromosomal disorders.

In addition to the genetic contribution, the environment often plays an important part in influencing both the onset and severity of disease, particularly in the polygenic disorders.

3.3.1.1 Single gene diseases
Inherited single gene diseases may show three common types of inheritance pattern.

1. Autosomal dominant: such diseases (Huntington's disease, for instance) result from one of a pair of matched autosomal genes having a disease-associated alteration, the other being normal. The chance of inheriting the altered gene from an affected parent is 1 in 2 in each pregnancy. Autosomal dominant diseases commonly affect several individuals in successive generations.
2. Autosomal recessive: these diseases (such as cystic fibrosis) require the inheritance from both parents of the same disease-associated abnormal autosomal gene. The parents are usually themselves unaffected, but are gene carriers. When both parents carry the same altered gene, the chance of inheriting two altered genes and thereby of having the disease is 1 in 4 in each pregnancy. Autosomal-recessive diseases usually only affect the brothers and sisters within a single generation; the incidence of the disease in individuals in previous or subsequent generations is usually very small. Hence diseases with this form of inheritance tend to occur 'out of the blue'.
3. X-linked: diseases due to genes on the X chromosome (such as haemophilia) show a special inheritance pattern: they are also known as sex-linked disorders. Most X-linked conditions occur only in males who inherit the abnormal gene from their mothers. These mothers are carriers of the altered gene but are usually unaffected themselves, because their other X chromosome has the normal gene (as in auto-somal-recessive disease). Females may occasionally show some features of the disease, depending on the condition. An affected male never transmits the disease to his sons. When the mother carries a gene for an X- linked disease, the chance of inheriting the altered gene is 1 in 2 in each pregnancy for both boys and girls, but only the male offspring will be affected. X- linked disease may thus give rise to the disease in males in several different generations, connected through the female line.

3.3.1.2 Polygenic disorders
Many common diseases with a genetic basis result from abnormalities in more than one gene. The inheritance pattern is complicated because of the larger number of different genetic combinations and uncertainties about how the genes interact. Environmental factors frequently play a major part in such disorders, which are more often known as multifactorial diseases. Because of this, screening can yield results that are less clear-cut. At the same time, as we advance our knowledge of all the environmental and genetic factors involved, it will become possible to identify individuals who are at increased risk of a disorder and who would benefit from advice on how to minimise the risk. This could lead to screening for genetic predisposition to common diseases, such as coronary heart disease, diabetes and some cancers.

3.3.1.3 Chromosomal disorders
Chromosomal disorders fall into two broad categories.

1. Where an entire chromosome is added or is missing. For example, in Down's syndrome there is an extra (third) copy of chromosome 21 found in the cells of affected individuals (hence the technical term for it, Trisomy 21). In Turner's syndrome, one of the X chromosomes in girls is missing. This type of disorder is not inherited but occurs during the production of a gamete (egg or sperm).
2. Rearrangement of chromosomal material. If this involves either net loss or gain of chromosomal material, harmful clinical effects are likely. On the other hand, if a simple exchange occurs between chromosomes (translocation) or within them (inversion), the chromosome make-up may be 'balanced', and serious clinical effects are much less frequent.

3.3.1.4 Types of genetic tests
All forms of genetic test aim to identify particular genetic characteristics but approach this in different ways.

3.3.1.4.1 Chromosomal tests (cytogenetics)
Microscopic examination of chromosomes from cells in blood, amniotic fluid or fetal tissue may be used to detect the chromosomal changes mentioned above. Until recent years it was possible to detect only large alterations on a chromosome involving many genes, but new techniques are making it possible to detect much smaller defects, allowing recognition of disorders involving only a small amount of genetic material.

3.3.1.4.2 Tests for disorders involving a single gene
Genes cannot be seen through the light microscope, so tests for single gene disorders have been largely indirect, involving what the gene produces (protein), or another substance affected by it, rather than the gene itself. The protein is still unknown for the majority of genes, so testing for single gene disorders has been very limited until recently.

3.3.1.4.3 Direct tests
Various techniques have been developed for identifying important human genes directly. The two main approaches are:

1. the gene may be isolated if the product (protein) it normally produces is known. This approach was used for the genes involved with the main blood cell protein, haemoglobin (important for tests involving sickle cell disease and thalassaemia). The genes causing some meta- bolic diseases, where a specific chemical defect involving an enzyme was already known, have also been isolated in this way;
2. the gene may be isolated if its position on a chromosome is known (positional cloning). This approach is increasingly successful in allowing genes to be isolated even when we know nothing about their function or what protein they normally produce. One reason for this success is that detailed genetic maps of the different chromosomes are being produced. This approach not only pinpoints the chromosome region where the gene lies, but can provide genetic markers (identifiable pieces of DNA) which lie close to the gene, and enables an accurate test for a genetic disorder to be made even before the gene itself is isolated.

Once the gene responsible for a disorder has been isolated, it is possible to study its different changes (mutations) that may result in disease. These range from complete absence of the gene to faults in a single chemical subunit of the gene. A single gene disorder may be caused by many different changes in the gene responsible. By careful study of particular populations of people it may be possible to determine which mutations for a disease are the commonest and most important, and to design a test programme accordingly.

Direct genetic testing by DNA techniques differs in several important respects from most other forms of medical testing. Any body tissue can be used since genes are present in almost all cells. Although blood is most commonly used, cells obtained by mouthwash are proving especially suitable for some screening programmes. Since genes do not usually change during life, a DNA test can be performed at any time from conception onwards. This is a practical advantage for tests in early pregnancy, as it allows the detection of a serious genetic abnormality that, otherwise, would not show itself until after birth. However, this raises difficult ethical problems, especially in relation to diseases that do not appear until later childhood or adulthood.

Major scientific advances have occurred in the sensitivity of genetic techniques, allowing minute amounts of DNA or protein products to be analysed. A particularly important advance has been the polymerase chain reaction (PCR), which allows a single copy of a small part of a gene to be amplified many thousand times. Testing of single cells may make preconception testing of a single egg feasible, and may also allow testing of fetal cells in the mother's blood during early pregnancy. The dried blood spot taken onto filter paper from all babies in the newborn period can be stored and used for a wide range of genetic tests. New techniques increase the potential impact of genetic testing, because they are often suitable for mass population screening.

An important discovery is that many stretches of normal DNA vary between different people and together provide a pattern that is unique for every individual (apart from identical twins). This powerful technique, known as genetic fingerprinting, has many applications, especially in legal cases. There are important ethical issues as to when and how it should be used.

3.3.1.4.4 Indirect (biochemical) tests
These tests do not detect the gene itself, but some aspect of its function. The most nearly direct tests are for the specific protein that the gene produces. In a genetic disorder, tests may show that the protein is not being made or is present in reduced amount; or that it may be altered so that it does not function adequately. Such tests are important; for example, for detecting abnormalities of haemoglobin (in thalassaemia or sickle cell disease).

Where the gene or its product cannot easily be tested, it may be possible to measure some other substance that is altered in the disease. Thus the screening test for the disorder phenylketonuria (PKU), commonly used in Britain and South Africa on all newborn babies, is based on measuring the amino acid, phenylalanine, which builds up in the blood of affected persons.

3.3.1.4.5 Ultrasound
A quite different but very important technique is ultrasound imaging, which gives a virtually risk-free method of identifying structural and some functional abnormalities that may result from genetic disease. This technique is widely used during pregnancy for the detection of fetal malformations, some of which are genetic in origin. Some early manifestations of serious genetic disorders that may develop in later life, such as polycystic kidney disease (enlarged kidneys with cysts) or certain types of cardiomyopathy (heart muscle disease) may also be detected.

3.3.2 Current screening programmes
In reviewing existing screening programmes, some of which are well established and others barely beyond the pilot stage, various ethical problems may arise.

Screening programmes are broadly divided into four groups, depending on the timing of the testing. These are:

1. neonatal (in the newborn);
2. older children;
3. testing of couples or individuals before pregnancy (adults); and
4. antenatal (during pregnancy).

There may be no single stage of life at which genetic screening is most suitable. Screening may best be offered in a variety of ways, and the optimal approach may change as the community becomes better informed. For example, genetic screening for thalassaemia in Cyprus and Sardinia (countries where this disorder is particularly common) has progressed from the antenatal stage to the premarital stage and towards screening in schools. This type of progression may prove to be a common pattern as genetic screening becomes a more established component of primary health care.

3.3.2.1 Neonatal screening
The blood spot test for phenylketonuria (PKU) has not created any major ethical problems. Likewise the test for congenital hypothyroidism, which is carried out on the same sample, does not appear to have raised any major ethical problems. This may be partly because both diseases are severe and can be adequately treated if detected.

Nevertheless, there is evidence that many women do not understand the purpose of the test. A study in Britain of new mothers' knowledge of the blood test for PKU and hypothyroidism, showed that two-thirds said that the test had been fully explained. Most, in fact, did not know what the test was for, and many incorrectly believed that it also detected other disorders. Such results clearly challenge any notion that women are giving informed consent for their babies to be tested, although they believe themselves to be informed. There is no reason to believe that South Africa would be any different.

Some laboratories carrying out neonatal screening for PKU and hypothyroidism, in Britain and in other countries, have chosen to add tests for other serious conditions. It is not always clear to what extent parents are fully informed about these tests. A neonatal screening programme in Pittsburgh, USA, has chosen to employ 'informed dissent', where parents are required to express a wish to opt out if they so desire.

The present method of screening for PKU, which is recessively inherited, is indirect and does not identify the genes involved. If direct gene testing were introduced, so that carriers as well as affected individuals were identified, a different order of ethical issues would arise. The finding of a carrier child has no disease implications for the child, but may become important to that child in later life, when reproductive decisions are being made. How and when the child should be told would require careful consideration.

Neonatal screening for sickle cell disease is cheap and reliable, and it is recommended for populations with a significant incidence of this disease. Early diagnosis of affected infants reduces childhood mortality and morbidity, and allows parents to be counselled about subsequent pregnancies. In some inner-city areas in Britain, all newborns, regardless of ethnic origin, are now screened for sickle cell disease. Screening, however, does detect carriers as well as affected individuals, and thus raises ethical issues for the families as discussed above.

Neonatal screening for cystic fibrosis (CF) by indirect testing (for trypsin in the blood) is carried out only in certain areas and is still under evaluation. There is some, but not conclusive, evidence that neonatal identification of infants with cystic fibrosis may improve their prognosis, because preventive management can be started before their lungs are damaged. Parents of affected children can also be offered prenatal diagnosis in subsequent pregnancies. DNA techniques, which identify carriers as well as affected children, have been used for confirmation of the diagnosis in the newborn period.

Pilot neonatal screening programmes for early identification of Duchenne muscular dystrophy have been set up in Britain (in Wales) and several other countries. All of these programmes have been based on an indirect method; the detection of the level of the enzyme, creatine kinase, in the blood. These programmes vary somewhat in detail, and in the manner of obtaining consent: the Pittsburgh study, for example, employs informed dissent. The X-linked nature of this disease raises particular ethical issues in terms of implications for the extended family.

Because neonatal screening for Duchenne muscular dystrophy is essentially still in the pilot stage, evaluation of all the ethical issues is not possible. Most workers involved consider that extensive, well-monitored pilot phases should precede a decision on more general implementations.

All newborn babies have a physical examination which may detect congenital disorders, some of which may have a genetic component. Examinations are often carried out in the presence of the mother, and the parents are informed about any abnormalities and their implications.

3.3.2.2 Later childhood screening
As part of routine child health surveillance, all children have a physical examination for a variety of diseases that may, in part, have a genetic basis. For example, hearing defects may be detected. Programmes of screening for specific genetic disorders are in the pilot stage. These need to adhere to the principles of informed consent (see 5.3 in Book 1).

3.3.2.3 Adult screening
Screening of adults may be carried out to detect existing disease or predisposition to a disease, or it may identify carriers with a reproductive genetic risk. Most presymptomatic testing for late onset genetic diseases (such as Huntington's disease) is currently offered to family members at risk. Increasingly, general screening for such late-onset genetic diseases is becoming technically feasible, although not necessarily desirable.

Screening programmes for various cancers that may have a genetic basis are currently the main form of genetic screening in the adult population. Testing the gene itself is now possible for familial adenomatous polyposis, an inherited form of colorectal cancer. It may soon be possible to screen a subgroup of women at high risk of familial breast cancer, although at present such screening is aimed at early detection of the cancer itself. These testing programmes in families already known to be at risk, may be the forerunners of future screening programmes.

The general screening of individuals who may be carriers of inherited disease genes is currently used only as a service to those in an ethnic group known to have a high incidence of an inherited disease; for example, the haemoglobin disorders in people of African, Mediterranean and South East Asian origin and Tay-Sachs disease in Ashkenazi Jews.

Pilot projects have been undertaken in several centres in Britain to detect carriers of cystic fibrosis in adults aged between 16 and 45 years through screening in general practice.

3.3.2.4 Pre-pregnancy and premarital screening
Testing before pregnancy is not systematically practised to any extent in Britain or South Africa. Screening for carriers of the haemoglobin disorders may be offered through family planning clinics and general practice. Insufficient information is available to evaluate these programmes.

In Cyprus, antenatal screening for thalassaemia has been almost totally superseded by premarital screening. The religious authorities had ethical objections to screening during pregnancy, on the grounds that it excluded most options other than termination of affected pregnancies. The church in Cyprus therefore insists on testing as a formal prerequisite to church weddings. The certificate required states merely that the partners have been tested and appropriately advised. In this way the confidentiality of the test result is preserved and the couple can exercise an informed choice about reproduction.

General population carrier-screening programmes for thalassaemia have been established throughout the Mediterranean area. A comparative study of these programmes has shown they are most rapidly and equitably implemented when a small community at high risk is served by motivated staff working from a single centre, with the help of a lay support association (for example, Sardinia and Cyprus). Such programmes have developed more slowly in larger countries, as they must be delivered through the general health care system, and staff must be trained to integrate screening and counselling into routine services. It has proved particularly difficult to organise carrier screening for haemoglobin disorders where they are not a problem for the whole community, but primarily affect ethnic minorities, as in Britain. This problem is the subject of the Report of a Working Party of the Standing Medical Advisory Committee on Sickle Cell, Thalassaemia and other Haemoglobinopathies.³¹ This report provides guidelines to health service purchasers and providers on the provision of information, screening and counselling services.

3.3.2.5 Screening during pregnancy
Screening during pregnancy may be carried out on the mother, on the fetus, or on both. If, through screening, a woman is found to be a carrier of a gene for a recessive disorder, her partner may be offered genetic testing to find out whether the couple is at risk of having an affected child. If both parents carry the gene for a recessive disorder, if the mother carries the gene for an X-linked disorder, or if either parent has the gene for a dominant disorder, tests may be done on the developing fetus. There are several methods of obtaining samples for genetic tests on the fetus, the most common being amniocentesis and chorionic villus sampling (CVS). Genetic diagnosis can be achieved before 12 weeks' gestation with CVS, compared with about 16-20 weeks by amniocentesis. However, the risk of miscarriage is slightly higher for CVS (about 1-2% in excess of expectation at this stage of pregnancy) than for amniocentesis (0.5-1%). The emotional trauma caused by the need to consider a termination and to decide whether or not to have one, must not be ignored. This is a major ethical issue that applies to many screening procedures where the disease is serious and where there is no effective treatment. Informing parents of the reproductive choices, places a considerable burden on them, and counselling and support will be needed - whatever the decision.

In Britain, antenatal screening tests are carried out on all women for a predisposition to rhesus haemolytic disease of the newborn and rubella (German measles). Rubella screening was the first screening programme undertaken with the objective of offering detection and abortion of potentially affected fetuses. Severe congenital disorders may result from rubella infection during pregnancy. Both rhesus and rubella screening appear to be well accepted. Whereas the finding of a rhesus negative blood group results in preventive treatment, a positive rubella test gives rise to the need for very painful decisions, including the termination of the pregnancy.

Ultrasound scanning of the fetus is generally practised, and routine ultrasound may reveal congenital abnormalities, some of which may have a genetic basis. Expert fetal anomaly scanning, a specialised form of ultrasound scanning, is offered to women known to be at increased risk of having a malformed fetus because of genetic or other reasons. In addition, it is increasingly offered to all women on a routine basis, as about 70-80% of all severe malformations can be detected by the technique. Although the majority of women are aware of ultrasound, the amount of explanation given regarding the possibility of detecting abnormalities varies greatly, as does expertise in interpreting the results.

The offspring of women with insulin-dependent diabetes mellitus have an increased risk of stillbirth, neonatal ill health and major congenital malformations, especially if their diabetes is poorly controlled. In many women with diabetes the diagnosis will already be known, but all women are screened early in pregnancy by blood and urine tests to detect undiagnosed cases. Expert fetal anomaly scanning by ultrasound is offered to all pregnant diabetics.

In many areas, screening is carried out to detect neural tube defects (spina bifida and anencephaly). Maternal serum alphafetoprotein (AFP) determination is now offered routinely to all pregnant women between 16 and 18 weeks of gestation, but in about half of all pregnancies with a raised maternal serum AFP, no cause can be found, either pre- or postnatally. A raised maternal serum AFP normally leads to expert ultrasound examination for a fetal malformation, with or without amniocentesis for confirmatory biochemical tests.

Pilot studies of screening during pregnancy for carriers of the common disorder, cystic fibrosis, are currently being undertaken in a number of centres in Britain, where 85- 90% of carriers can be detected by a simple DNA screening test based on a mouthwash sample.

The various studies of cystic fibrosis screening have devoted considerable effort to the psychological and ethical issues surrounding genetic screening programmes, especially since not all carriers can be detected.

Antenatal screening is offered to women in specific risk groups. All women over an age that varies by area between 35 and 37 are offered testing by chromosome studies for the presence of Down's syndrome in the baby. Down's syndrome occurs in approximately 1 in 600 of all births; but is much less common in children born to younger women (1 in 1 500 at age 20). Its birth incidence increases with maternal age, being about 1 in 350 at age 35, and as high as 1 in 100 at age 40. Recently, maternal serum screening tests have been developed that can be offered to all pregnant women, regardless of age, to detect those who may be at increased risk of having a child with Down's syndrome, in order to offer the choice of amniocentesis and chromosome testing. Unfortunately, only just over 60% of affected babies will be detected in this way and 5% of the screened pregnancies will give results necessitating an amniocentesis, to reassure the participating women that they are not carrying a fetus with Down's syndrome.

3.3.2.6 Practice implications
Health professionals must recognise women's fears that the unborn baby might have a serious abnormality and their need for information about the implications where such a diagnosis is confirmed. Further, protocols concerning the implementation of screening programmes should include adequate psychosocial support for participants.

3.3.3 Counselling, providing information and obtaining consent
Genetic counselling is the provision of accurate, full and unbiased information that individuals and families require to make decisions in an empathetic relationship that offers guidance and assists people to work towards their own decisions.³² The information should include a full description of the risks, diagnosis, symptoms and treatment of the disorder in question. Information about financial costs, emotional costs, education, and both positive and negative effects on the marriage and family unit should be included, as well as available social and financial supports for persons with genetic conditions.¹⁴

It is fundamental that actual knowledge or understanding on the part of the patient, or person consenting on behalf of the patient, is achieved. It is not sufficient for the practitioner to have reasonably explained the information. Informed consent is valid only when it represents true understanding.¹⁴ This rigorous test of consent is linked to the patients' right to be so informed that they understand the proposed test or procedure, the possible alternatives and any associated risks, to enable them to make a balanced judgement on whether to continue with the test or procedure or to withdraw.¹⁴ Evidence suggests that the combination of written information supplemented with face-to-face interaction is the most desirable method of ensuring that patients receive sufficient information to empower them to make this choice.²⁶ It must be clear at all stages of the screening that the participant or patient is free to withdraw from the process at any time (see 5.3 in Book 1).

It is recommended that the following ethical principles should be applied to genetic counselling:

1. respect for persons, families and their decisions according to the principles underlying informed consent;
2. preservation of family integrity;
3. full disclosure to individuals and families, of accurate, unbiased information relevant to health;
4. protection of the privacy of individuals and families from unjustified intrusions by employers, insurers and schools;
5. informing families and individuals about possible misuses of genetic information by institutional third parties;
6. informing individuals that it is their ethical duty to tell blood relatives of the genetic risks to which they may be exposed;
7. informing individuals about the wisdom of disclosing their carrier status to a spouse or partner if children are intended, and the possibility of harmful effects on the marriage from non-disclosure;
8. informing people of their moral duty to disclose a genetic status that may affect public safety;
9. unbiased presentation of information, insofar as this is possible;
10. adopting a non-directive approach, except when treatment is available, although the person being counselled may still decline treatment;
11. involving children and adolescents whenever possible, in decisions affecting them; and
12. observing the duty to re-contact if appropriate and desired.³²

Informed consent is an accepted norm in the clinician-patient relationship, implying the patients' knowledge of the major characteristics of their medical disorder, an understanding of the test or procedure they are to undergo, the limitations of the test or procedure, and the possible consequence of their participation in the test or procedure followed by their agreement, or not, to undergo the test or procedure.¹⁴ This term includes a right on the part of the participants or patients to be informed of risks not actually related to the medical impact of the test or procedure, including:

"Possible socio-economic consequences of an unfavourable test result, such as loss of health or life insurance, refusal of employment, discrimination by schools, adoption agencies etc. should where applicable, be included under the description of risks."¹⁴

It is recommended, further, that information to be given to any patient undergoing genetic screening should include:

1. the seriousness of the condition to which the genetic disorder may give rise and how variable its effects are;
2. the therapeutic options available;
3. how the disorder is transmitted, the significance of carrier status and the probability of development of the serious genetic disease;
4. the reliability of the screening procedure and the results of the test;
5. information detailing how the results of the screening test will be passed on to the patient, and what will be done with the samples;
6. the implications of a positive result for their future and existing children and for other family members;
7. a warning that the screening test may reveal unexpected and awkward information; for example, about paternity.²⁶

3.3.4 Genetic screening - the law and public policy
The negative impacts of genetic screening may be separated into two categories of harm. The first is the effect on the personal choices and mental well being of the individual, and the second is the effect on the interaction of that individual with society at large. The first category of harm may include increased personal anxiety about health, decisions related to the termination of pregnancy, and deciding whether to pass on genetic information to spouses, partners or family members.²⁶ The second category involves more powerful ethical considerations with regard to eugenics, employment prospects and access to life insurance and other benefits. It is with this second-category harm that we are primarily concerned in these guidelines.

3.3.4.1 Results of genetic screening and confidentiality
Genetic information can be effectively used to reduce the health-related cost of labour. This simple fact is the most powerful reason for employers and insurers to be interested in genetic screening and testing. On the other hand, the dissemination of genetic information to employers and insurers may be linked to the dangers of "isolation, loss of insurance, educational and job opportunities for persons diagnosed with incurable and costly disorders." ²⁸

Dangers associated with genetic screening differ from those associated with genetic testing. Genetic screening is carried out at the instance of the State or large institutions, while genetic testing is done at the instance of the individual being tested. Guidelines related to genetic screening should also govern the scope and aim of screening programmes and ethical aspects relating to the use, storage and registration of data and follow-up procedure,²⁸ while guidelines for genetic testing should be more focused on aspects pertaining to the individual and the protection of his or her rights.

3.3.4.1.1 The scope and aim of screening programmes
"The literature on genetic screening and discrimination suggests several areas of sensitivity:

1. the workplace, where employers may choose to test job applicants, or those already employed, for susceptibility to toxic substances or for genetic variations that could lead to future disabilities, thereby raising health or compensation costs. In terms of Section 7 of the Employment Equity Act, No. 55 of 1998, medical testing of employees or job applicants by employers is prohibited in South Africa unless legislation permits or requires testing, or it is justified in the light of medical facts, employment conditions, social policy, the fair distribution of employee benefits or the inherent requirements of a job. Medical testing includes any test, question, inquiry or other means designed to ascertain, or which has the effect of enabling the employer to ascertain, whether an employee has any medical condition. Medical testing could therefore include some types of genetic testing;
2. the insurers (either life or health insurance companies) who might use genetic information or tests as criteria for denying coverage or require reproductive testing to be done for cost containment purposes. In terms of the South African Medical Schemes Act No. 131 of 1998, a registered medical aid scheme may not unfairly discriminate directly or indirectly against its members on the basis of their "state of health"; and,
3. law enforcement officials, who may test and/or use information without informed consent."²⁸

It is trite to state that employers and insurers should have limited rights to initiate screening programmes. This alone will not prevent genetic discrimination from occurring for so long as employers and insurers have access to genetic information.^j

3.3.4.1.2 Test results, privacy and data protection
Every individual undergoing either genetic screening or genetic testing has the right to be fully informed of the results concerning a suspected disorder.²⁶ A difficulty arises where an individual is to be informed of results that are "unexpected, unwanted, and have not been covered by consent. For example, a sex chromosome abnormality may be revealed when carrying out prenatal testing for Down's syndrome, or a different inherited disease may show up on a test designed for another purpose. Unexpected information can present ethical dilemmas for which there are no easy answers, or indeed correct answers."²⁶

Article 8(l) of the European Convention on Human Rights provides that 'Everyone has the right to respect for his private and family life, his home and his correspondence'. The right to private life, or to privacy, clearly includes the right to be protected from the unwanted publication or disclosure of intimate personal information. The South African Constitution clearly protects each individual's right to privacy. Section 14 of the Constitution and the common-law right to privacy include privacy of information; that is, the right to determine for oneself how and to what extent information about oneself is communicated to others.

These general principles are particularly important in medicine. Respect for privacy is vital to the clinician/patient relationship. The relationship must be built on trust and confidence if patients are to reveal information essential to the proper diagnosis and treatment of their condition. Yet trust and confidence would soon be shattered if clinicians were to fail to respect the confidentiality of intimate personal information.

The case for confidentiality in medicine applies with equal force to genetic screening. Individuals agreeing to be screened need to be confident that no results will be made available to anyone other than themselves and their medical advisers, without their explicit consent. Otherwise, people may be reluctant to participate, perhaps with damaging implications for themselves, their families and, potentially, other third parties. If clinicians were to break the confidence relating to genetic information, there would be adverse implications for other areas relating to the care and treatment of the patient. The patient would fear that other medical information was being disclosed to a third party.

The rights to privacy generally, and to the confidentiality of personal medical information in particular, are of the greatest importance, but it does not necessarily follow that both should be wholly unqualified. Article 8(2) of the European Convention on Human Rights provides, for example, that the individual's right to personal privacy may be overridden by requirements prescribed by laws introduced to protect health, morals, or the rights and freedoms of others. Section 36 of the South African Constitution also provides for the limitation of rights by laws of general application, to the extent that the limitation is reasonable and justifiable in an open and democratic society, taking into account various factors. These provisions may be particularly important in genetic screening.

The decision of an individual to participate in a genetic screening or testing programme may have implications for other family members, which could affect their future. The question is whether there is an obligation on the part of health professionals to consider the interests of the family members, even if the participating individual does not wish to warn relatives who might be at risk. The HUGO Ethics Committee in a statement on DNA Sampling: Control and Access, states that the "shared biological risks [of family members] create special interests and moral obligations with respect to access, storage and destruction that may occasionally outweigh individual wishes."³³

The issue is a contentious one, because the claims of family members may vary in strength. An individual may have an interest in knowing whether a partner or prospective partner is likely to suffer from, for instance, familial colon or breast cancer, or Huntington's disease. But such an interest, while understandable, falls far short of any right to demand knowledge. The emphasis is somewhat different if having children with a particular partner is contemplated. For example, a pregnant woman may legitimately want to know the result of the screening test on the father of her child, if she herself has had a positive test, indicating that she carries a gene for cystic fibrosis or Tay-Sachs disease. A different problem may arise with blood relatives, where non-disclosure of information might lead to an unnecessary termination, or where a relative, not informed of a high genetic risk, might become the parent of a child with a serious genetic disorder. A more difficult case is made out for siblings and other blood relatives who face the same risks in respect of a genetic disorder or disease, and may well have an interest in the outcome of the screening results.

3.3.4.1.3 The ethical dilemmas
We discuss first the responsibility of the individual in resolving the dilemmas, and next, the role and responsibility of the clinician or other professional adviser. The main ethical dilemma arises from a conflict between the right of the individual to personal privacy, and the reasonable desire of family members to be fully informed. The information, after all, might play a part in important decisions about their lives. A balance needs to be struck between the two. A further complicating factor, though, is that some family members may prefer not to be presented with the information. This would become a much more serious problem if widespread screening were introduced for X-linked or autosomal dominant diseases.

The individual's responsibility
The question of responsibility has at least two dimensions here. The first is the responsibility of the individual to pass on relevant information to other family members, and the second is the responsibility of the other family members to receive the information. We adopt the view that a person acting responsibly would normally wish to communicate important genetic information to other family members. These members may have an interest in the information, and a responsible person would probably wish to receive it, particularly where it might have a bearing on decisions that he or she may take in the future. We are also of the view that the primary responsibility for communicating genetic information to a family member or other third party lies with the individual and not with the clinician, who may, however, do this at the request of the person concerned.

Where family members do not wish to know, the situation may be more difficult. If family members were unaware that a relative had been screened, they would not know whether or not they wanted to be informed about the result. In these circumstances the individual who had been tested might have to inform them - or not inform them - personally.

Although serious problems may arise as a result of non-disclosure, and certain family members may have a legitimate interest in the information, this should not always supersede the individual's right to privacy. It is difficult to contemplate how any such legal obligation would apply, and how any legal right of family members (assuming that they could be identified) could be enforced. South African law does not impose a general duty to inform, but the community values (boni mores) may demand disclosure, to inform potentially identifiable persons within easy reach, who might suffer serious harm.k In any event, in certain circumstances there may be perfectly good reasons why an individual would not wish to inform family members about the result of a genetic test. For example, a woman who has discovered she is a carrier of Duchenne muscular dystrophy may not wish to tell her sister who is 7 months pregnant.

The best way to ensure that genetic findings are appropriately shared with family members (and occasionally with other third parties) is through information and counselling procedures. Disclosure to other family members ought not to be made a condition of participation in a screening programme. Inevitably some individuals will refuse to allow disclosure and this may present the clinician or other health professional with an ethical dilemma.

The clinician's dilemma
Just as we have rejected the suggestion that there should be a legally enforceable duty placed on people who have been screened, to inform family members or other third parties of the results, so too we reject the idea that clinicians should be placed under a legal duty to reveal information against the wishes of the individual concerned. No such general duty is acknowledged by law in this country, although the position may be different elsewhere. The furthest the law appears to go is to recognise that in exceptional and ill-defined cases the clinician may have discretion to disclose genetic information to third parties (see 3.3.4.1.2).

Privacy and confidentiality should be respected and maintained, but we also accept that there may be exceptional circumstances in which these might properly be overridden by the clinician; for example, where information is withheld out of malice. We do not suggest that the wishes of the individual should be overridden only in this type of case. However, it illustrates how exceptional are the situations in which it may be appropriate and reasonable to subordinate the individual's privacy to the interests of others.

It is impossible to foresee all the circumstances in which a doctor might properly disclose confidential information to family members. Although a set of guidelines and a knowledge of the law may be helpful, the decision on disclosure is also made according to the facts of each case. See in this respect the ethical guidelines of the South African Medical Association on HIV/AIDS (1998) and those of the Health Professions Council of South Africa (1994), which make provision for disclosure of a patient's HIV status.

This imposes a heavy burden of responsibility on the health professional. Two factors stand out as especially relevant. The first is the consequence of the refusal to share information. There would be a stronger case for overriding individuals' objections where consequences of disclosure are potentially damaging, rather than merely inconvenient to other family members. The second factor is the reason for the individual's refusal to permit disclosure. If it can be determined that the reasons are malicious, the decision may be straightforward. However, if the reason was a fear that the information might yield compromising evidence about paternity, the ethical issues would be quite different. If information about non-paternity was not disclosed, a man who incorrectly believed himself to be the father of a child with a particular genetic status might make the wrong decisions about having other children. On the other hand, for the health professional to reveal such information might lead to harm to the woman concerned, not only because of the breach of confidentiality itself, but also because of its impact on the woman's relationship with the man involved. For this dilemma there is no easy answer.

It is recommended, therefore, that the following points be adopted as guidelines to disclosure, to families, of the results of a genetic screening programme:

1. "the accepted standards of the confidentiality of medical information should be followed as far as possible;
2. where the application of such standards might result in grave damage to the interests of other family members, the health professional should seek to persuade the individual to allow disclosure of the genetic information. The potential seriousness of non-disclosure should be explained to the individual;
3. in exceptional circumstances, health professionals might be justified in disclosing genetic information to other family members, despite an individual's desire for confidentiality."²⁶

3.3.4.1.4 Genetic registers
In the context of genetic screening, where large numbers of tests are undertaken, this may be recorded in the form of a genetic register or similar database. Special consideration should be given to the implications for security of these grouped results.

A register may be defined as a systematic collection of relevant information on a group of individuals. Genetic registers record information on individuals with specific genetic disorders, and may include relatives at risk of developing or transmitting the condition. The information may be recorded by hand, or may be held on computer. Genetic registers may be set up for a variety of reasons, including research on the disorder, the effective provision of services to those on the register, and the systematic offer of genetic counselling to family members. The amount and type of information recorded varies greatly, as does the presence of identifying details.

There are several general ethical issues concerning genetic registers. Here we outline issues relating to genetic screening. They should be seen against the background of the following points:

1. a genetic register may be the starting point for genetic screening; for example, the systematic testing of relatives of individuals with fragile X syndrome or Duchenne muscular dystrophy;
2. genetic screening may also be based on a register not specifically genetic in its basis; for example, registers of specific cancers or of those with severe learning difficulties;
3. a genetic register may be the product of a genetic screening programme; for example, a register of carriers of cystic fibrosis or sickle cell disease in a population screened for the purpose.

It is essential to obtain individuals' consent before placing their names on a register. It is also important that individuals know that they are on the register, and what use will be made of the information.

Consent of individuals to long-term storage of information resulting from genetic screening has been emphasised earlier. However, if this is to form the foundation of a genetic register, separate and specific consent should be sought for subsequent tests or other measures, also for further use which may generate financial benefits for the investigator.

Confidentiality of all medical information is essential, and this is particularly the case with genetic registers, which may contain highly sensitive and potentially identifiable data on large numbers of individuals with, or at risk of, serious genetic disorders.

Computer-based genetic registers are subject to the Promotion of Access to Information Act, No. 2 of 2000, but there is need for additional safeguards for all genetic registers, including secure storage of information, limitation of access to those specifically responsible for a register, and the removal of identifying information when data are used for research purposes. Further, a Data Protection Act is envisaged for South Africa.

This is an important area of concern. The Department of Health, in consultation with health authorities and appropriate professional bodies, should devise effective arrangements for the preservation of confidentiality, particularly in relation to genetic registers, and should provide the necessary guidance.

3.3.4.2 Employment
Competition drives the players in the economy to reduce costs and increase efficiency. In the context of employment, genetic screening provides the employer with an opportunity to reduce the health-related costs of employment. An employer may want to screen candidates, to exclude those susceptible to either occupational or non- occupational disease.

"Healthy workers cost less: they are less often absent through illness, there are lower costs for hiring temporary replacements or for training permanent replacements, and there are fewer precautions which would need to be taken to deal with health and safety risks."²⁶

The dangers of permitting employers to embark on their own screening programmes are self evident. The result would be restrictions on the employment of individuals who are at risk of genetic disease, and the creation of class orders based on genetic disposition. In other words, genetic discrimination would ensue. Wealth most often follows employment, education follows wealth, and employment follows education: a neat circle ensuring comfort for those within its exclusive confines. The cost implications for the State are critical. Whereas the business community currently bears some of the costs of genetic disease in the population, by excluding this cost through genetic screening, business would effectively shift the their share of the cost to the State, with repercussions for social welfare and health policy in particular.

However, employees and the public at large have an interest in reducing the incidence of occupational disease. It is accepted that employers may require employees to undergo screening for illnesses or conditions that present a serious danger to third parties.26 Thus genetic screening may have a limited role to play in employment. One way of achieving this is for the State to introduce screening programmes whereby individuals are made aware of their genetic disposition and are empowered to make informed decisions with regard to their employment and their health.

Section 7 of the Employment Equity Act. No. 55 of 1998, prohibits the medical testing of employees and applicants for employment, unless legislation permits or requires testing, or it is justifiable in the light of various factors, such as employment conditions or the inherent requirements of the job.

3.3.4.3 Insurance
Insurance and risk management are two separate forms of practice. Risk management seeks to reduce the costs associated with risks that will certainly eventuate, whereas insurance is more like a gamble: it is unknown whether the event will occur or not. The relevance of this to genetic screening is that at present the medical aid industry operates as a form of insurance. Insurers constantly try to determine the risk associated with potential clients, to better allocate the premiums and so attract the least risky clients.

The revolution in genetics allows insurers to reduce uncertainty about future events. This fundamentally changes the context of insurance. The more predicable the risk, the more accurately an insurer can apportion premiums. The repercussions for individuals with genetic predispositions to certain diseases are that they may not be granted health insurance at all, or may be charged higher premiums. It has to be borne in mind that The Medical Schemes Act, No. 131 of 1998, provides that a registered medical aid scheme may not unfairly discriminate directly or indirectly against its members on the basis of their 'state of health'.

However, insurers have argued that using genetic information to predict risks is nothing more radical than an extension of their current practice. At present, insurers require people seeking insurance to provide information regarding their family medical history and lifestyle, to be able to predict the risks and thereby to determine an appropriate premium. Further, insurers require insurance applicants to disclose all known information that would impact on the risk - this would include disclosure of both an HIV positive status and the results of genetic tests. It is thus argued that the additional information obtained from genetic tests is an extension of accepted practices.

At face value, the argument is persuasive. However, the results of genetic tests do not always predict outcomes, but are rather a test for a certain mutation.

"Additional statistical information linking a given test result to the occurrence of some disorder is also needed if a sound prediction of disease or of lowered life expectation is to be made on the basis of a genetic test result. Without information that links genetic test results to incidence of disease or death, they lack actuarial import."³⁴

There is information linking the existence of certain single gene disorders to the onset of a genetic disease or lowered life expectancy. However, it is not clear whether the relevant test predicts the onset of the disease or establishes the presence of the disease.³⁴ Insurers require predictive test results, but even those predictive tests that are available cannot accurately determine the onset of the genetic disease.

Recommendations on the use of genetic screening and genetic tests by insurance companies arise from the following considerations:

1. the difficulty of assessing sometimes slender evidence on the genetic susceptibility of individuals to develop polygenic and multi-factorial diseases (for example, some cancers and some forms of heart disease);
2. an awareness that ordinary commercial practice will lead companies to be overcautious in their assessment of the risks derived from medical data; and
3. the possibility of abuses.

3.3.4.4 Children
There are well-founded reasons for testing asymptomatic children and adolescents for genetic diseases or carrier status. However, genetic testing of children raises ethical concerns over issues such as informed consent and disclosure to the child. The test is conducted only where it is in the best interests of the child; thus the primary justification for the test should be timely medical benefit to the child.³⁵ If the provider of the test is of the view that the potential harm of the test would outweigh the potential benefit, or if medical intervention would be of no benefit until adulthood, the test should be deferred until adulthood.³⁵

There is a presumption of parental authority in our law, which acknowledges the child's lack of the capacity to make appropriate life-impacting decisions, and that parents are usually best placed to decide about the well-being of their child, and have the greatest interest in promoting their children's well-being.³⁵ The assent of the child should be sought. Related to this right is the right to make an informed decision without interference from health-care providers, although this right can be limited where there are objective reasons to believe that a decision or action has significant potential for an adverse impact on the health or well-being of the child.³⁵

The following recommendations of The American Society of Human Genetics and the American College of Medical Genetics Report³⁵ in respect of family involvement in decision-making are endorsed:

1. education and counselling for the parents and the child, according to the child's maturity, should precede genetic testing;
2. the test provider should obtain the permission of the parents and the assent of the child or the consent of the adolescent. In terms of the Child Care Act, No. 74 of 1983, a child above the age of 14 years may consent independently to medical treatment, which would include genetic testing from which the child could benefit directly (see 5.3, Book 1);
3. the test provider is obliged to advocate the child's best interests at all times;
4. a request by a competent adolescent for the results of a genetic test should be given priority over the parents' requests to withhold information.