Belgian Society of Human Genetics :

Guidelines for predictive genetic testing for late onset disorders

March 2003

These guidelines for good practice apply to predictive genetic testing of adults who are at risk of developing a specific and serious hereditary late onset disease and who are capable of making an informed choice. Susceptibility testing for multifactorial late onset disorders will not be considered in this document. The guidelines do not apply to community screening for genetic disorders (that is, screening people who do not have a significant family history). We assume that the test will have been validated and is capable of giving reasonably definite predictions.

Predictive testing, including presymptomatic testing, using DNA (or in some cases RNA, protein,…) is becoming available for many disorders. Clinical geneticists and genetic counsellors, together with many other health care professionals, are aware of the impact these findings can have on individuals and their families. Experience in offering this service to people, such as to those at risk of Huntington's disease, has been accumulating over recent years. However, with the growth of both knowledge and technology, there are progressively more situations where testing is possible. New groups of health professionals and potential test users have to become familiar with these tests and the context in which they are used.


Differences between genetic tests and other tests in medical practice

Most medical tests are able to detect evidence of a disease process that is already present and can help to resolve its nature. Some (eg. sensitive imaging techniques) may detect changes in those at risk before symptoms occur, but they still reflect an early stage of the pathological process. There is some blurring between genetic tests and other tests that are able to detect very early pathological changes in individuals at risk for an inherited late onset disorder. Some other tests in clinical practice can indeed be used as less direct markers for genetic disorders eg. serum lipids in familial hypercholesterolaemia and imaging studies for structural changes in adult polycystic kidney disease. This report’s definition of genetic testing (“Testing to detect the presence or absence of, or alteration in, a particular gene, chromosome or a gene product, in relation to a genetic disorder”) is a purposefully wide one. However we consider that genetic tests, particularly those based on analysis of the genetic material itself (DNA), differ from other tests in a number of ways:

a) Since the DNA a person inherits and passes on remains largely unchanged throughout life, genetic testing for inherited disorders, based on analysis of DNA, can potentially be carried out at any point from conception to old age.

b) Hence DNA testing needs only be performed once. Its results remain valid throughout lifetime.

c) The presence or absence of an abnormality in a genetic test is unaffected by whether the individual has symptoms of the disease or not.

d) Since DNA is present in most body cells, any tissue sample can be used for a test for inherited disorders. Blood or mouthwash samples are examples.

e) DNA is extremely stable, and can be analysed using stored samples taken for other purposes or post mortem samples.

f) Genetic tests for inherited disorders differ from most other clinical tests which only involve a single individual, because they may also reveal important information about relatives and can have a great impact on families.

There are some distinctive features of genetic PREDICTIVE TESTING:

a) They have the potential to predict with considerable scientific confidence the possible future health of an asymptomatic individual. This has particular significance in relation to employment and insurance.

a.1) Since the genetic change underlying late onset disorders can be identified at any age, there may be an interval of years or even decades between a healthy individual being tested and the onset of the disease. It is also being increasingly recognised that even for some disorders following a clear cut inheritance pattern, a proportion of those showing the genetic change may remain entirely healthy.

a.2) Predictive genetic testing raises serious issues, and some of these may be more complex than those faced in other clinical areas. The test result, which has implications as well for the family as for the tested individual, may cause anxiety or alleviate concerns in an otherwise healthy individual. Therefore the consultation before and after a genetic test to explain the implications and consequences of the result, may be different from that needed in many other types of medical tests or treatments. Persons tested -, and possibly their family need to understand the nature of the test results that may be expected and their consequences before the tests are performed. Confidentiality must be appropriately protected but the probable implications for family members need to be understood by the person consenting to genetic testing.


Scientific and clinical validity of the predictive genetic tests

Like for all medical tests the scientific and clinical validity should be established. When genetic tests are validated scientifically, the following needs to be established before a predictive test is used in clinical practice.

a) The error rate and failure rate should be known and explained to those requesting a predictive test. It is of the utmost importance that persons to be potentially tested receive all relevant information about the test, including the limitations of a test, error and failure rate. This should be explained to the persons before performing the test in the laboratory. It could possibly influence the decision to be tested or not. It is necessary to recall these issues when the results of the test are available.

a.1) When an abnormal genetic test result is obtained it usually does not allow any clear prediction of severity or age at onset. However some specific mutations are found to be associated with more or less severe disease. Age at onset has likewise been found to be statistically associated with the extent of the genetic change in some mutations that are variable in size, as seen in Huntington’s disease and myotonic dystrophy. This type of information may be extremely important to those tested, but it should only form part of the test result as given to the individual if the associations have been validated and if the information can be used in interpreting an individual result rather than an overall series. The information should, if requested, be provided as part of post-test counselling.

a.2) The disorder and specific mutation being analysed should be confirmed in an affected family member. If confirmation is not possible the implications of an "apparently" normal result should be clearly explained. These will vary according to the disorder involved.


Genetic laboratories

Like for all other genetic tests, laboratories providing a predictive genetic testing service should be formally recognized for this and take part in internal and external quality control schemes. Predictive genetic testing should be done on duplicate samples and the results must be analysed on different days and both results must be the same.
Predictive genetic testing should be undertaken only by the laboratories being part of a medical genetics department which can provide full genetic counselling with a multidisciplinary team (genetic counsellor, psychologist or psychiatrist,…). Many clinical laboratories use genetic techniques to investigate disease, and the detection of somatic (non-inherited) genetic changes forms an important part of laboratory analyses of tumours. Although the technologies may be the same, genetic testing for inherited disorders, in particular predictive testing, requires different approaches, and should be reserved to recognized molecular genetic laboratories. Research laboratories should not normally be the basis for a genetic testing service. Occasionally the genetic centres may ask research laboratories to perform a specific analysis because of the rarity of the disorder or other factors.


"Over the counter" predictive genetic testing

"Over the counter" genetic testing is totally inappropriate for late onset diseases and should be strongly discouraged.


Consent to predictive genetic testing

In the case of predictive genetic testing of healthy individuals, (preferably written) informed consent should always be obtained. Written consent is not in itself a substitute for careful face to face explanation. If another genetic analysis is to be carried out at a later stage, consent is again required for that genetic test.


Principle of autonomy

The principle of autonomy relates to a person's ability to make or exercise a self-determining choice. The decision to undertake the test is the sole choice of the person concerned. The person must choose freely to be tested and not be coerced by family, friends, potential spouses, physicians, insurance companies, business concerns, governments, etc. No requests from third parties, be they the family, medical doctor or otherwise, shall be considered. Predictive testing in childhood removes the possibility of that individual to make an autonomous decision as an adult. (see predictive testing in children and adolescents, below).


Information needed by those requesting predictive genetic testing

The communication of various types of information outlined in this section comprises a considerable part of the process known as genetic counselling which is given by a clinical geneticist in the context of a multidisciplinary setting:

a) Information on the disorder being tested should be full, accurate and appropriately presented, in a clear and simple manner that is readily understandable. While some individuals requesting predictive genetic testing for a late onset disorder will have extensive experience of the condition from their own family, others will not, or the information may be incomplete. This information is essential if individuals are to make appropriate decisions regarding testing. Information should be provided in an understandable form. Written information is recommended.

b) Full information should be provided on the test, its consequences and limitations, and its scientific and clinical validity.
Some individuals being tested may have inaccurate expectations as to what a predictive genetic test can deliver in terms of removing or confirming a risk, or in predicting severity or age of onset. This may also apply to some clinicians requesting tests. A predictive test cannot predict severity or age of onset. Individuals should be fully informed on consequences for themselves (all consequences should be discussed: being a carrier, not being a carrier or not taking the test), the spouse/companion, the affected parent and his/her spouse (the feelings of the affected parent, who may be aware of the result, must be taken into account), other family members (whatever information is obtained, it will influence the feelings of and the relationships with other relatives). Furthermore, predictive genetic testing may give information on family members who have not themselves requested testing and it may affect them directly or indirectly. Thus an abnormal result in a person at 25% risk for a serious genetic disorder (a person with an affected grandparent and an asymptomatic parent), would imply that the intervening healthy parent would also be likely to develop the disorder, even though they did not wish testing. Thus conflicts may arise between one person’s right to know and a relative’s right not to know. Whenever possible such implications need full discussion with both parties before testing.

c) Individuals should be fully informed of potential adverse consequences, such as for insurance and employment.
Experience with predictive genetic testing for Huntington’s disease and other serious late onset disorders has shown that while many individuals are well informed in advance, there are almost always significant issues that have not yet been considered and which are important to enable them to make an appropriate decision.

d) While written information is important, complex information should be provided face to face by an appropriately trained and experienced person. In predictive genetic testing for serious late onset disorders, there are frequently complex and sensitive issues that require discussion, rather than mere provision of information. Nurses, social workers, psychologists, psychiatrists and other professionals may play an important role in pre- and post-test counselling or home visiting to ensure that necessary support can be provided and that information has been received and understood.

e) Patient support groups and lay organisations involved with genetic disorders can also be a valuable source of information for those considering genetic testing.

f) Individuals should be given adequate time to absorb the provided information before taking a decision regarding testing or being given a result. For serious late onset disorders, such as familial cancers and Huntington’s disease, a two step approach has been found to be important in allowing time for reflection. Since a premium is often placed on avoiding delay in other laboratory testing situations, it is important that this time interval is protected.


Support in relation to predictive genetic testing

a) Appropriate support in preparation for and subsequent to genetic testing should be considered as part of the genetic testing process.

Genetic testing for late onset disorders may have consequences extending many years ahead and affecting multiple family members. The testing process itself may also be extremely stressful, but experience from Huntington’s disease and familial cancers suggests that even serious adverse results can usually be well coped with if the person tested is fully prepared and has adequate support. The likely needs for support should be considered and planned for as part of the testing process, otherwise unexpected serious problems could be generated for the individual, for family doctors and for other staff.

b) Consideration should be given to the cost of the potential support needs for genetic tests when evaluation and commissioning genetic services.
The cost of associated genetic counselling and related measures should be estimated in addition to and separately from the laboratory aspects of a genetic test. Some genetic tests for late onset disorders, such as that for polyposis coli, may avoid other costly, and for the patient potentially risky, investigations if individuals thought to be at risk can be shown to be free from the relevant genetic mutation. The potential effects of abnormal test results in terms of long term support and medical investigations also need to be considered when the likely overall benefit of the test is being assessed.


Psychological counseling in the context of predictive genetic testing:

Psychological counselling should be provided in the pre-and post-test stage of predictive testing. The major objectives of the pre-test counselling are: providing emotional support, clarifying the person’s test motivation and test expectations, facilitating the decision making process and anticipating possible problems in the post-test period. Moreover, the communication about the genetic disease within the family should be stimulated and facilitated; possible communication problems should be identified and discussed.
Follow-up counselling should pay attention to the possible negative psychological consequences for the tested individuals and their family. It should also pay attention to the individual’s preventive health behaviour in case of an unfavourable test result. If preventive surgery is considered, additional psychological counselling should be provided before and after surgery.


Necessity of protocols:

For each type of disease a written protocol respecting the guidelines and principles formulated in this document should be established and available for predictive test applicants and professionals.


Prenatal and preimplantation genetic testing for late onset disorders

Prenatal genetic testing for late onset disorders should only be undertaken in the context of full genetic counselling.
Requests for prenatal genetic testing are relatively uncommon for late onset disorders by comparison with serious childhood genetic disease. In general, requests are normally related to severe and untreatable disorders, where the individual concerned has experienced particular adverse effects of the disorder. Prenatal testing can also provide an option for those healthy individuals with an abnormal presymptomatic test result to have children free of the genetic disorder in question. There may be complex situations when a person simultaneously requests presymptomatic genetic testing for themselves and for their pregnancy.
Although it is not offered in all centres, prenatal “exclusion testing” may be considered. For example, a woman at 50% risk of developing Huntington’s disease may wish to exclude the disorder in a pregnancy, whilst not wishing to know her own genetic status. Here the pregnancy is tested to determine whether the parent at risk has passed on the genotype of the affected or unaffected grandparent, without testing for the specific genetic change associated with the disorder. This would either raise the risk for the foetus to 50% or exclude the risk. Thus only 50%, not 100%, of interrupted pregnancies would really carry the mutation.
A particular issue arises when a couple decides to continue a pregnancy after an abnormal prenatal test result. This results in knowing that the child to be born will be affected later in life while in principle no predictive testing for an untreatable disease is performed in children in order to respect their autonomous decision making (see predictive testing of children). Although this may be an inevitable occurrence on occasions, full discussion in advance of prenatal testing is of utmost importance to avoid this situation.

Preimplantation genetic diagnosis for late onset disorders should only be undertaken in the context of full genetic counselling. So far requests have been limited but they increase and they mainly come from asymptomatic individuals who had an unfavourable predictive test result, occasionally from a person with minor symptoms. Embryos shown to carry the mutation should never be transferred to the uterus.
Preimplantation exclusion testing (a very recent possibility not offered in all centres) may be considered by at risk individuals who did not apply for predictive testing. Embryos shown to be at risk should not be transferred to the uterus.


Predictive testing in children and adolescents

The clear and defined benefit for the child should be the paramount consideration. The principle is that predictive testing of minors (children under 18) should only be considered where the test result is likely to be of direct benefit to the child through medical surveillance or intervention or preventive actions. Predictive testing of children should not be performed at the parents’ request without the child’s knowledge and participation in the counselling process.

As a consequence the working group agrees with the general consensus against predictive testing of healthy minors for untreatable disorders of (usually) adult onset, e.g. Huntington’s disease. The decision about predictive testing for such conditions has to be made by the autonomous at-risk adult, after appropriate counselling. It is essential to preserve the right not to know until they are competent to make a free informed decision. It is not excluded that exceptionally some adolescents who approach the age of legal majority and who request a predictive test themselves may be able to make such a decision before 18 years of age.

Predictive testing of minors for disorders in which direct medical benefits can arise from knowledge of the genetic status during childhood is justified. In this context familial adenomatous polyposis is a good example. In this condition surveillance is recommended from about the age of 12 years as childhood onset has been well documented. Here at-risk minors who are tested for the mutation and who do not have the mutation can be reassured and discharged from follow-up. Minors with the mutation should have regular colonoscopic surveillance and prophylactic surgery when appropriate. Adequate counselling of child and parents in a genetic centre is necessary. In principle predictive testing should only be available at the age that is considered as adequate for starting medical surveillance.

These guidelines were elaborated by a Working Group of the Belgian Society of Human Genetics:

Chair: Prof. Gerry Evers-Kiebooms

Secretary: Prof. Marc Abramowicz

Members: Dr Maryse Bonduelle, Dr Marleen Decruyenaere, Prof. Anne De Paepe, Dr Nicole Van Regemorter, Prof. Miikka Vikkula

After the Annual meeting of the BeSHG all members were invited to comment and these comments resulted in the present revised version.

The above recommendations address predictive testing for mutations with high penetrance.
Guidelines for predictive testing for low penetrance (e.g., 20%) monogenic disorders as well as for susceptibility testing for multifactorial diseases are also needed.



Addendum: Definitions


Diagnostic Genetic Testing : Use of genetic testing in a symptomatic individual to aid in diagnosis, treatment and management.

Predictive Genetic Testing : Testing primarily carried out in healthy or asymptomatic individuals to provide information about that individual’s future health, with respect to specific inherited diseases. Such a test result may indicate that the individual has a high likelihood of developing the disorder or of excluding it.

Susceptibility Testing : Testing which provides information about the genetic components in a multifactorial disorder . Multifactorial disorders are disorders whose genetic components are not the sole causes, but which work with other, often environmental factors, in determining a disease outcome. They include many cardiovascular diseases, most Alzheimer’s disease of old age and some forms of diabetes.

Genetic counselling: A process of consultation by which information is imparted to individuals or families affected by or at risk for a genetic disorder. It includes information on the nature of the disorder; the size and extent of genetic risks; the options, including genetic testing, that may help clarify the risks; the available preventive and therapeutic measures, and the provision of psychological, social and practical support. In the context of genetic testing it may include responding to the concerns of individuals referred and their families, discussing the consequences of a test, and enabling them to choose the optimal decision for themselves, but not determining a particular course of action.