Abstract
Objective
To examine whether the experience gained in offering various genetic tests may be of help in the planning for screening in schools for a personality profile that may identify those destined to develop schizophrenia.
Method
To examine the outcomes in offering genetic testing: (i) to individuals at risk of developing Huntington's disease; (ii) to school pupils for carrier status for cystic fibrosis; and (iii) to the intellectually handicapped in schools to identify those with the fragile X syndrome.
Results
All programs however carefully planned, encounter the unexpected and unforeseen.
Conclusions
It is essential to know the specificity and sensitivity of your screening test; to ensure that all have adequate knowledge before consenting to the testing; to ensure the confidentiality of the test results to the individual being tested and their families; and to ensure that funding is adequate and ongoing to provide continuing support and therapy to the families identified when research converts to service.
Physicians tend to fall into two groups. The majority are conservative and wait for patients to recognise that they have a problem and then provide a service. A minority are those who feel more evangelical, believe that they have something very definite to offer and wish to identify people who might benefit from their help before they themselves recognise they need it. These are the screeners; they want action. The more cautious conservatives tend to raise all the ethical issues. The papers presented at this conference are from both types and discuss the possibility of screening secondary school populations for a presymptomatic personality profile that is predisposed to the development of psychiatric illness in the hope that medication may be preventive. The present paper describes some of the experiences encountered when offering various forms of genetic screening to different populations.
One of the earlier genetic screening programs was to offer predictive testing to the first-degree relatives of individuals affected with Huntington's disease (HD). There were many issues raised, such as the sensitivity and specificity of the test; how should test results be given out?; what sort of guidelines should we use for offering gene testing?; and were people going to commit suicide if they found that they had the gene for the disease? There were all sorts of gates to be negotiated before an individual could be tested. They were required to fill out a lengthy questionnaire. In addition to seeing the clinical geneticist, they had to be assessed by both a psychiatrist and a neurologist. This was followed by a period of time when they were reviewed by a genetic counsellor in order to make sure they really wanted the information the test might provide. There was much discussion over problems of confidentiality, employment and life insurance. Much of this early caution has now vanished, with no dire consequences.
Presymptomatic testing for HD did have several unanticipated findings. The suicide rate was found to be lower in those who learnt that they had the gene for HD than in those who had been at 50% risk before specific gene testing had become available. Such people found that the stress of not knowing whether they were going to get the disease was much worse than the certainty that they were, in fact, liable to develop HD. Another surprise was that some of those who were particularly stressed were those that were found not to carry the mutation and so were not at risk of HD. They had lived their lives anticipating that they were going to get HD and now had to adjust to fundamentally altered expectations.
A survey carried out of patients in the Hunter Region, who had been through testing, found that the worst part of testing was waiting for the results. Another finding was that no more than 45% of people who were at 50% prior risk wanted more specific information; they made an informed choice not to be tested. We believe that it is most important to respect the individual's autonomy in these matters so that he or she can say freely ‘I do’ or ‘I do not want this test’. This is important when considering offering a preventive program in schizophrenia, particularly in schoolchildren who may not appreciate fully the consequences of testing.
Another screening program we have undertaken was testing individuals in schools for the fragile X syndrome. This is a type of moderate to severe intellectual handicap. It is caused by a mutation on the X chromosome so that it primarily affects the male, but female relatives are at risk of being carriers. The program was developed because we had shown that the fragile X syndrome was significantly underdiagnosed so that females in the extended family were unaware of their risks of having affected children. Screening at that time was by the direct examination of the karyotype requiring a sample of blood. This seemed a reliable test, but its sensitivity or specificity were not known.
We were required to obtain ethics approval from the New South Wales Education Department (Australia) and then from each school principal, followed by informed consent for a physical examination and a blood test from the parents and, finally, verbal agreement for the blood test from the handicapped individuals themselves. It looked an impossible task! However, the Education Department was most helpful and only one of the many school principals in New South Wales refused to cooperate. Some 76% of parents or guardians consented and the pupils themselves nearly all agreed to the blood test. We were surprised by this high uptake. It should be stressed that we obtained informed consent from parents with the objective of informing the relatives but that the latter were not the ones giving consent.
There were some unanticipated problems. Part of the planned physical examination included the measurement of testicular size as one criteria in the decision to do the blood test. The testes are larger than normal in those with the fragile X syndrome. However, that part of the physical examination was immediately found to be unacceptable and so was stopped in the first school we visited. Later it was appreciated that the specificity of the chromosomal test was less than we had assumed so that there was overdiagnosis of the fragile X syndrome, which resulted in our publishing a prevalence rate that was twice as high as the reality. This was revealed when specific molecular testing became available. We learnt how difficult it is to undo a diagnosis once made. Follow-up of the program showed that, in a large sample of both the immediate and extended members of the fragile X families, 85% were most grateful for the new diagnostic and genetic information.
One unanticipated consequence of this type of program is that one accumulates an increasing number of patients with long-term problems who continue to need a service. Screening starts in the name of research but steadily moves from research into service. Any program identifying a group of people who need a continuing service cannot assume that continuing support will be available through routine community services. They are used to you as a person and they come to expect you to help them. We now manage 250 families with the fragile X syndrome in which there are over 1000 carrier females. It is essential that, in planning a screening program, funding or provisions must also be established for ongoing management.
One of the other screening programs we have run was testing for carriers for cystic fibrosis in secondary schools. One in 25 of the Caucasian population are carriers. Cystic fibrosis is inherited as an autosomal recessive disease so that if you are a carrier and you know your partner is a carrier then there is a 1 in 4 risk of having a child with cystic fibrosis. It follows that screening the community for carriers is one way to prevent cystic fibrosis as this provides information for parents to make informed choices when they consider having children. One mutation is common, ΔF 508, which accounts for 75% of all the mutations, but a negative result when testing for this one common mutation does not exclude you from being a carrier.
We used a DNA test on a simple mouthwash, which is more acceptable to secondary school students than a venepuncture. We found an 80% uptake in girls but 20% in boys and a marked difference in different schools, which appeared to be dependent on the personality and enthusiasm of the school principal. The main theoretical ethical concern we encountered was the fear that a student found to be a carrier would become labelled as such and feel, or be, stigmatised. However, this did not happen. The main practical ethical concern was the age at which students could give their own permission to be tested without parental approval.
Planning screening for a predisposition to schizophrenia needs to include knowing the natural history of the disease, which would inform about at what stage a screening test can be expected to be positive and what the chances are that a negative test at the age of testing is a true negative. The test needs to be short to administer, reliable and independent of the intelligence of those being tested. The test needs to be specific. You may be looking for a predisposition to schizophrenia but the test may identify other conditions as well. The test's sensitivity, specificity and positive predictive value need to be known. Also important are the dollar costs of testing and follow-up interviews to confirm results.
Consider the population to be screened. Do you offer screening to all and, if so, at what age? Do you screen only those identified with a behaviour disorder? How will you define those with behaviour disorders? Who defines the behaviour problem: the teacher's or counsellor's reports or the view of the parents or the teenagers own concerns about themselves? All of these are, in their own right, a form of screening test and should be considered in the same way as the more specific tests.
There is a need to obtain consent to testing. It is essential to be totally upfront with the schools, the parents and the pupils. Few will have heard of schizophrenia and none will believe that the present behaviour, even accepted as a problem, could lead to such a devastating disease. How many parents will permit their children to be put on mind-altering drugs? What may be needed is an extensive education program about schizophrenia for all school staff and the community that the school serves.
One strategy might be to start with those with a positive family history. However, I should caution that a ‘positive family history’ needs proper medical confirmation. For example, in the investigation of familial breast cancer, we often find that the firmly held view of the consultant, that the operation her aunt had was for breast cancer proves, when the documentation is complete, to have been a benign lumpectomy.
There are also ethical problems, in particular, confidentiality. When testing in the sensitive area of behaviour and personality, it needs to be quite clear to all from the start who shall have access to the information obtained. Our experience in the schools was that the principals and teachers wished to know results. We let them know numbers but never names.
Post-screening support services may well be needed by some of those who have been tested as well as those regarded as ‘positive’ on testing. It is of practical and ethical importance to keep track of all that is done, and measure the results: If any form of treatment is given, then it needs to have either a control group or be done as a double-blind study if medication is involved.
Screening programs are not simple and straightforward. There are difficulties, but these should not be a deterrent but rather a stimulant. There comes a time when you have to get your feet wet.
The cause of schizophrenia remains a mystery but traditional twin and family studies clearly indicate a major genetic component. Some families have been reported with multiple affected members who have had DNA linkage studies. Nothing conclusive has been found. There is an association with the velo-cardio-facial or Shprintzen syndrome, which is caused by a deletion on chromosome 22 and an association with abnormalities on the short arm of chromosome 15. However, this can only account for a tiny fraction of the problem. Schizophrenia is likely to be heterogeneous and may result from the interactions of mutations in several different genes producing a similar clinical picture.
One possibility is the abnormal expansion of a triplet-repeat sequence as found in some diseases affecting other neurological systems; for example, myotonic dystrophy, the fragile X syndrome and HD. The clinical phenomenon of anticipation is found in these conditions and has been suggested in some families with schizophrenia. Another possibility is a two-hit mechanism that has been very rewarding in the understanding of such diverse conditions as retinoblastoma, familial bowel and breast cancer, and polycystic kidney disease. Here it is believed that the affected individual has a mutation in one of the paired autosomal genes inherited from his or her parents. This is asymptomatic, only affecting one allelle; however, when a second hit or somatic mutation occurs in the second allelle, disease becomes manifest. Second ‘hits’ occur naturally, a normal effect of ageing, genetic fault in DNA repair mechanisms, random radiation and chemical or dietetic exposure. Somatic mutations become evident after some 10–30 years so that the familial form of the disease appears earlier in life than the nonfamilial form. To date this theory has been most successful in explaining early-onset familial malignant diseases. There is no theoretical objection to applying it to schizophrenia. The traditional genetic aetiology for schizophrenia is that it is ‘multifactorial’, meaning a result of the interaction of one or more genes with one or more environmental factors. It is a word used when geneticists do not know.
In the future answers will emerge. Molecular tests will probably provide reliable markers for some subpopulations of schizophrenia. I think with the new FISH techniques we will find other patients with schizophrenia as well as the velo-cardio-facial syndrome, who have a chromosomal abnormality. New diagnostic tests will be devised, which we cannot presently envisage, and drug therapies may be developed that are tailored to specific subtypes of schizophrenia.
In conclusion, I have some concern about a screening program defining ‘normality’, and subjecting those falling outside the two standard deviations to mind-altering drugs. And who decides? The idea of a homogeneous, well-adjusted mass of schoolchildren is surely death to creativity. It raises the question about how many of us might have been selected for medication?