Predictive and pre-natal testing for Huntington Disease in Australia: results and challenges encountered during a 10-year period (1994-2003)

This study summarizes 10-years' experience of predictive and pre-natal testing and pre-implantation genetic diagnosis (PGD) for Huntington disease (HD) in Australia. Results are presented from 2036 direct mutation predictive tests conducted between January 1994 and December 2003. Thirty-eight per cent of results (776/2036) were positive, 56% (1140/2036) were negative, and 6% (120/2036)) were in the mutable normal (27-35 CAG repeats) or in the reduced penetrance (36-39 CAG repeats) ranges. Ninety-four per cent (1908/2036) and 6% (128/2036) of those tested had prior genetic risks of 50% and 25%, respectively. Twenty-seven per cent (34/128) of those at 25% risk had their genetic status changed to positive, thus revealing the positive status of their at-risk parent. During this period, 63 pre-natal tests were also conducted, and 13 children were born following PGD for HD. Social workers specializing in predictive testing counselling over this 10-year period across Australia identified and summarized particularly challenging counselling issues. These included the interpretation of mutable normal and reduced penetrance range test results, potential conflicts of interest between family members regarding testing decisions, unanticipated consequences of both predictive and pre-natal testing decisions, the importance of following protocols for predictive testing to facilitate long-term adjustment to results, and the potential for genetic discrimination. The identified issues highlight the importance of the protocols for predictive testing and indicate that extension of the international guidelines published in 1994 may be timely.     

Predictive testing of 25 percent at-risk individuals for Huntington disease (1987–1997)

Before the mutation causing Huntington disease was identified, predictive testing of 25% at-risk persons with a 50% at-risk parent who did not wish to know his/her genetic status, was only possible by exclusion testing. The exclusion test, using linked markers, ensures the parent's wish not to know because the parent's risk is not changed. When mutation analysis became available in 1993, new testing options for 25% at-risk persons emerged: viz., the exclusion-definitive test and direct mutation analysis. These new tests not only disclose the risk of the test candidate, but may also change the risk of the at-risk parent and siblings. The testing options for 25% at-risk test applicants and their consequences are discussed and the testing procedures and results of testing 64 25% at-risk persons in the period 1987 to 1997 are described. Relatives received unsought information in 56% of the test procedures before and 34% after the mutation was identified. A decision tree and guidelines for predictive testing of 25% at-risk test applicants are proposed. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:662–668, 1999. © 1999 Wiley-Liss, Inc.     

22 Years of predictive testing for Huntington's disease: the experience of the UK Huntington's Prediction Consortium

Huntington''s disease (HD) is a progressive neurodegenerative condition. At-risk individuals have accessed predictive testing via direct mutation testing since 1993. The UK Huntington''s Prediction Consortium has collected anonymised data on UK predictive tests, annually, from 1993 to 2014: 9407 predictive tests were performed across 23 UK centres. Where gender was recorded, 4077 participants were male (44.3%) and 5122 were female (55.7%). The median age of participants was 37 years. The most common reason for predictive testing was to reduce uncertainty (70.5%). Of the 8441 predictive tests on individuals at 50% prior risk, 4629 (54.8%) were reported as mutation negative and 3790 (44.9%) were mutation positive, with 22 (0.3%) in the database being uninterpretable. Using a prevalence figure of 12.3 × 10⁻⁵, the cumulative uptake of predictive testing in the 50% at-risk UK population from 1994 to 2014 was estimated at 17.4% (95% CI: 16.9–18.0%). We present the largest study conducted on predictive testing in HD. Our findings indicate that the vast majority of individuals at risk of HD (>80%) have not undergone predictive testing. Future therapies in HD will likely target presymptomatic individuals; therefore, identifying the at-risk population whose gene status is unknown is of significant public health value.     

Predictive testing for Huntington disease in a developing country

Predictive testing for Huntington disease (HD), by means of direct mutation analysis, has been offered at the Division of Human Genetics, University of Cape Town, from 1995. The aim of this study was to compile a comprehensive profile of the participants who had undergone predictive testing in the Western Cape from 1995 to 2005. The sociodemographic data, uptake and outcome of tests were analyzed to inform changes to improve the current genetic counseling services. A retrospective cross-sectional design using a 'multi-method' approach of both qualitative and quantitative methods was used. Data were gathered from the participants' hospital files and genetic database. Psychosocial data were obtained by face-to-face interviews with the participants in their homes or venues of choice. A total of 36 predictive tests were performed. The uptake for predictive testing was approximately 4.5% of the estimated at-risk population. The cohort of 27 individuals comprised 16 females and 11 males. Their mean age was 35.3 years; 6 were mixed ancestry and 21 were White people (European ancestry); 11 tested gene positive, 15 gene negative and 1 was in the reduced penetrance range. The most important issue identified was that the uptake of individuals classified as mixed ancestry was substantially lower than that of the White people possibly due to limited access to the predictive testing program because of the low levels of income and education in the general population of families with HD. Strategies to address these aspects have been incorporated into the program and will be reassessed after 1 year.     

Ten years of presymptomatic testing for Huntington's disease: the experience of the UK Huntington's Disease Prediction Consortium

Data on all presymptomatic genetic tests for Huntington's disease (HD) in the UK have been collected over the 10 year period since testing became available as a service. A total of 2937 completed tests have been performed up to the end of 1997, 2502 based on specific mutation testing, feasible since late 1993.
A total of 93.1% of these were at 50% prior risk, with a significant excess of females (58.3%); 41.4% of results were abnormal or high risk, including 29.4% in subjects aged 60 or over. The trend in test numbers has currently levelled out at around 500 per year.
Almost all presymptomatic tests are carried out in National Health Service genetics centres, with a defined genetic counselling protocol and with availability now in all regions of the UK. The introduction and establishment of HD presymptomatic testing shows that this form of predictive medicine for Mendelian disorders can be successfully incorporated into National Health Service structures. The comprehensive collection of simple data allows trends in demand and outcomes to be monitored and has also been the foundation for more detailed specific studies. A comparable approach to data collection in other genetic disorders will be important as presymptomatic testing becomes more generally feasible.


Keywords: Huntington's disease; presymptomatic testing     

Predictive testing of 25 percent at-risk individuals for Huntington disease (1987-1997)

Before the mutation causing Huntington disease was identified, predictive testing of 25% at-risk persons with a 50% at-risk parent who did not wish to know his/her genetic status, was only possible by exclusion testing. The exclusion test, using linked markers, ensures the parent's wish not to know because the parent's risk is not changed. When mutation analysis became available in 1993, new testing options for 25% at-risk persons emerged: viz., the exclusion-definitive test and direct mutation analysis. These new tests not only disclose the risk of the test candidate, but may also change the risk of the at-risk parent and siblings. The testing options for 25% at-risk test applicants and their consequences are discussed and the testing procedures and results of testing 64 25% at-risk persons in the period 1987 to 1997 are described. Relatives received unsought information in 56% of the test procedures before and 34% after the mutation was identified. A decision tree and guidelines for predictive testing of 25% at-risk test applicants are proposed. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:662-668, 1999.     

Predictive testing for Huntington''s disease: after the gene. The United Kingdom Huntington''s Disease Prediction Consortium.

The discovery of a mutation responsible for Huntington's disease (HD) offers the possibility of accurate predictive testing, as well as hope for treatment or prevention of this disease. We urge caution in the use of this new test as considerable ethical and counselling problems still exist, and new issues have arisen. The current guidelines for predictive testing should still apply, since it remains vital that subjects and their families have time to come to terms with the diagnosis of HD, and the implications of testing. Mutation analysis may allow the diagnosis of HD in isolated cases, or reverse a test result produced using linkage. Problems will arise as those at 25% risk may now receive a result despite the lack of support of their parent at 50% risk who may not wish to have their own status defined. In addition, couples who seek the exclusion test in pregnancy may find it difficult to investigate the pregnancy without producing information on themselves. Different centres should cooperate in maintaining the confidentiality of family members, ensuring that adequate counselling is given before results are produced which may affect the wider family.     

Predictive testing for Huntington disease: social characteristics and knowledge of applicants, attitudes to the test procedure and decisions made after testing

An investigation has been made of the social characteristics and knowledge and experience of Huntington disease (HD) for the first 80 individuals considering presymptomatic testing (applicants) at the medical genetics centres in Edinburgh and Glasgow and of attitudes to the test procedure and decisions made after testing for those who received a result. Sixty-one percent of applicants were female and 31% were over 40 years old. Almost all had a symptomatic parent but 38% did not know HD was in their family until they were over 25 years old and 48% had never received genetic counselling. Thirty-eight percent of applicants first heard of the test at the genetic clinic, 20% from a relative and 20% from the media, but none had received information from their GP. Thirty-one applicants did not have the test because they voluntarily withdrew (17 individuals), their family structure was unsuitable or no informative result was possible (11 individuals), or they were diagnosed clinically as being affected (3 individuals). Those who voluntarily withdrew did not differ significantly from the 49 who received a result in social characteristics or knowledge and experience of HD. Twenty-two individuals were found to be at increased risk (IR) (>50% of becoming affected) and 27 to be at decreased risk (DR) (< 50% of becoming affected). There was a median period of 9 months between entering the test procedure and receiving a result and the main criticism of the procedure was that it took too long to complete and several individuals experienced considerable anxiety while awaiting their result. One year after receiving their result, almost 40% of individuals had made major life decisions, mainly in the areas of personal relationships, career and financial matters and over a third of fecund individuals in both IR and DR groups had changed their decision about future childbearing. Eighty-five percent of the IR group and 53% of the DR group requested continued follow up after the 1-year follow-up visit. The majority wanted follow up by the genetic clinician, but we have found that in practice many individuals do not attend when offered clinic appointments after this time.     

Predictive testing for Huntington's disease: I. Predictors of uptake in South Wales

In Wales, predictive testing for Huntington's disease (HD) has not been offered proactively to families and uptake of testing is low in comparison to other centres. Little is known of those not requesting testing, particularly those not in direct contact with the genetics service. This study examined differences between a cohort of 22 test applicants and a random group of 32 'non-requesters', drawn from the South Wales HD register. Respondents were interviewed by means of a semi-structured schedule in their own homes. The study groups differed significantly on a number of variables including: knowledge of the availability of testing; perceived attitudes of family members and significant others to testing; length of knowledge and perceived stressfulness of being at risk; and perceived ability to cope with an unfavourable result. Overall, knowledge of testing procedures was poor and at-risk individuals' understanding of genetic terminology was at odds with scientific distinctions. Discussion focuses on the organisational and psychological factors associated with lack of knowledge of the availability of testing and the interpretation of reported coping capacities.     

Prenatal testing for Huntington's disease: a European collaborative study

This European study involving seven genetic centres from six countries - Aberdeen, Cardiff (UK), Leiden (Netherlands), Leuven (Belgium), Paris (France), Rome (Italy), Athens (Greece) has gathered information on prenatal testing by direct mutation analysis and exclusion testing for Huntington's disease (HD) from the six European countries during the period 1993-1998. Data describing the parent belonging to the HD family was collected; this included their sex and age as well as their risk of developing HD. Information about previous pregnancies, the rank of the pregnancy being tested and its outcome was also gathered. In addition the number of previous prenatal tests for HD was recorded. Three hundred and five results were recorded by the participating countries between 1993 and 1998. The largest groups came from the UK (157) and the Netherlands (90). The mean age for the parent from the HD family was 30.8 years. In half of the tests the prospective parent was an asymptomatic gene carrier, 42% remained at risk, and 6% of the prospective parents were already showing clinical features of HD. 65% of tests performed used mutation analysis.     

Uptake of Huntington disease predictive testing in a complete population

Using the Northern Ireland Huntington disease (HD) register, the number of prospectively recorded predictive tests was analysed over a 20-year period. Two hundred and twelve patients completed predictive testing. Ninety-two (43%) received mutation-positive results and 119 (56%) mutation negative. There was one intermediate allele result. There was no significant gender difference. One hundred and eighty affected cases confirmed by molecular genetic testing were alive on 1 January 2001. The uptake of predictive testing in the entire HD 50% at-risk population in 2001 was calculated by three methods giving a range of 12.3-14.6%. Uptake after 20 years was estimated to be 14.7%. The minimum prevalence of affected HD cases was calculated as 10.6/100,000 in 2001. The total uptake of predictive testing was calculated and it suggests that a substantial number of at-risk patients do not come forward for testing until symptomatic. Pre-symptomatic testing for this late-onset condition with no present treatment, and limited management options, still presents challenges for families.     

Teebi hypertelorism syndrome: Further observations

There are currently different research programs in place to assess the effects of predictive testing for a few late-onset disorders, including Huntington disease (HD) and familial cancers. Prior to providing predictive testing as a service, we sought the views of both the patients and the clinicians as to the importance and value of different items in a research protocol for HD. We mailed questionnaires to 41 clinicians and 351 at-risk patients who had participated in the research protocol, to solicit their opinions on the relative importance of various components of the HD predictive testing research protocol. Completed questionnaires were received from 256 patients (73%) and 33 clinicians (80%). Most participants (96%) were satisfied with the program, and <3% of persons receiving a modification of risk felt that predictive testing had impaired their quality of life. While there was consensus on the importance of most components of the protocol, significantly more clinicians than patients (97% vs. 72%; P =0.02) felt it was essential to keep written material about HD as part of a service protocol. More patients than clinicians (83% vs. 27%) considered it essential to have 24-hr contact numbers following disclosure of test results (P < 0.0001). Patients also felt more strongly about the importance of counseling about technical aspects of predictive testing (84% vs. 77%; P < 0.02), and about having a support person attend counselling sessions with the patient (62% vs. 48%; P = 0.04). Nearly 25% of participants indicated that they would not want their general practioner routinely involved in the predictive testing program. These findings have influenced the development of our service protocol, and they underscore the importance of involving both providers and consumers of predictive testing in the development of a service protocol for genetic testing. © 1995 Wiley-Liss, Inc.     

Psychological functioning before predictive testing for Huntington's disease: the role of the parental disease, risk perception, and subjective proximity of the disease

BACKGROUND: Psychometric testing of participants in predictive DNA testing for Huntington's disease (HD) has shown that 15% of the subjects at risk for HD had at least mild depression or a high score for general anxiety or both in the pre-test period. The main aim of the study was the delineation of variables associated with pre-test distress of applicants for predictive testing for HD. Based on theoretical considerations, four specific hypotheses were tested regarding the role of (1) the test participant's age at the (perceived) parental onset of HD, (2) the affected parent's sex, (3) the perception of the risk for HD, and (4) the subjective proximity of the disease. Secondly, these four variables were used in multiple regression analyses to select the best predictors of pre- and post-test psychological functioning (one year after the test). Increasing the understanding of pre- and post-test distress is important for developing better counselling and support strategies for test applicants. METHODS: Data were collected by means of clinical interviews and psychometric questionnaires during the pre- and post-test (one year after the test) counselling sessions for predictive testing for HD. RESULTS: We found significant associations of the participant's age at the parental onset, the subjective proximity of the disease onset, and the perceived risk with pre-test psychometric measures of psychological functioning. Multiple regression analyses showed that the best predictors of pre-test functioning were the perceived proximity of the disease onset and its interaction with risk perception. Regarding post-test functioning, none of the proposed variables had a unique contribution beyond that accounted for by pre-test psychological functioning. CONCLUSIONS: Test participants who are close to the perceived age of onset of HD and who have a pessimistic risk perception should be given special attention during pre-test counselling because of their possible negative affective condition at that time. Pre-test psychological measures were the best predictors of post-test distress, irrespective of the test result. Suggestions for future longitudinal research are formulated. This kind of research should enable clinical geneticists and mental health professionals to refine the pre- and post-test counselling strategies for predictive DNA testing, not only for HD, but also for other incurable late onset disorders.     

Managing genetic discrimination: strategies used by individuals found to have the Huntington disease mutation

The introduction of predictive testing for Huntington disease (HD) over 20 years ago has led to the advent of a new group of individuals found to have the HD mutation that are currently asymptomatic, yet destined in all likelihood to become affected at some point in the future. Genetic discrimination, a social risk associated with predictive testing, is the differential treatment of individuals based on genotypic difference rather than physical characteristics. While evidence for genetic discrimination exists, little is known about how individuals found to have the HD mutation cope with the potential for or experiences of genetic discrimination. The purpose of this study was to explore how individuals found to have the HD mutation manage the risk and experience of genetic discrimination. Semi-structured individual interviews were conducted with 37 individuals who were found to have the HD mutation and analysed using grounded theory methods. The findings suggest four main strategies: "keeping low", minimizing, pre-empting and confronting genetic discrimination. Strategies varied depending on individuals' level of engagement with genetic discrimination and the nature of the experience (actual experience of genetic discrimination or concern for its potential). This exploratory framework may explain the variation in approaches and reactions to genetic discrimination among individuals living with an increased risk for HD and may offer insight for persons at risk for other late-onset genetic diseases to cope with genetic discrimination.     

Reluctance to undergo predictive testing: The case of Huntington Disease

The development of a presymptomatic test for Huntington Disease (HD) has enabled some persons at risk to determine whether or not they are gene carriers. The purpose of this study was to explore the reasons why those at risk choose not to be tested in a situation where testing is available and most of the test-associated costs are covered by state funding. Subjects were also asked their levels of knowledge about testing, attitudes towards aspects of the testing protocols, and intentions towards testing once the gene for HD is found. Sixty-six individuals at risk for HD who had chosen not to be tested completed a mailed questionnaire. The most important reasons for not being tested were increased risk to children if one was found to be a gene carrier, absence of an effective cure, potential loss of health insurance, financial costs of testing, and the inability to “unndo” the knowledge. Individuals comprising this sample were quite knowledgeable about predictive testing. Most supported the availability of testing despite the lack of a cure, the need for special counseling prior to testing, and the idea that testing should be a voluntary decision. Most said they would take the test if a treatment was available, if the mechanics of the test were simplified, or if the test was 100% accurate. The risk to relatives, lack of treatment or cure, fear of losing one's health insurance, and the accuracy of the information to be gained from testing are important factors in the decision not to be tested. © 1993 Wiley-Liss, Inc.     

Attitudes of persons at risk for Huntington disease toward predictive testing

Attitudes of 69 persons at risk for Huntington disease (HD) were obtained by means of semistructured interviews and questionnaires. About 79% of the individuals said that they would use a presymptomatic predictive test if it were available. All believed that the test should be made available even though there was no cure for HD. Nearly 2/3 of subjects would use the test for prenatal diagnosis, and of these 71% would terminate a pregnancy if the fetus was found to carry the HD gene. Most subjects believed that pretest counseling should be mandatory and many said that testing should be withheld from persons who were psychologically unstable or were threatening self-harm. The data suggest that about 2-6% of persons at risk for HD may have severe psychiatric or suicidal responses to a positive outcome of predictive testing. This underscores the need for adequate pretest counseling and the availability of professional and community resources to deal with the impact of predictive testing on individuals and their relatives.     

Psychological consequences and predictors of adverse events in the first 5 years after predictive testing for Huntington's disease

The promise of genetic medicine is to provide information, based on genotype, to persons not yet sick about their risk of future illness. However, little is known of the long-term psychological effects for asymptomatic persons learning their risk of having a serious disease. Predictive genetic testing for Huntington's disease (HD) has been offered for the longest time for any disease. In the present study, the psychological consequences of predictive testing were assessed prospectively in individuals at risk for HD during seven visits over 5 years. Questionnaires of standard measures of psychological distress (the General Severity Index of the Symptom Check List-90-Revised), depression (the Beck Depression Inventory), and general well-being (the General Well-Being Scale) were administered to the participants. A significant reduction in psychological distress was observed for both result groups throughout 2 years (p < 0.001) and at 5 years (p = 0.002). Despite the overall improvement of the psychological well-being, 6.9% (14 of 202) of the participants experienced an adverse event during the first 2 years after predictive testing that was clinically significant. The frequency of all defined adverse events in the participants was 21.8%, with higher frequency in the increased risk group (p = 0.03) and most occurring within 12 months of receiving results.     

Psychological costs and benefits of predictive testing for Huntington's disease

The impact of predictive genetic testing for Huntington's disease (HD) was assessed in 68 persons at high (n = 17) or low risk (n = 51) for the disease at one to six years following disclosure of test results. There was consensus in both groups that knowledge of HD genetic status was beneficial. A majority of persons felt relief from wondering and uncertainty. High-risk persons identified greater family closeness and financial security. For low-risk persons, the knowledge that their children were spared offered great consolation. Negative effects in high-risk persons were psychological burden (worry, guilt). Even for low-risk subjects, there was a period of adjustment and, in some, disappointment that low risk had not alleviated problems unrelated to HD. Although the majority of marriages were unaffected by testing, some persons in both groups reported that their marriages sustained positive or negative impact. Despite mixed consequences, most did not regret being tested. The benefits of testing appear to outweigh its drawbacks, at least among this self-selected group of research participants. We also must conclude, however, that predictive genetic testing will result in negative as well as positive consequences, regardless of test outcome. © 1994 Wiley-Liss, Inc.     

Intended use of predictive testing by those at risk for Huntington disease

Huntington disease (HD) is a late-onset genetic disorder that is incurable and undetectable until the onset of symptoms. A marker for the gene that causes HD was recently discovered that will lead to a predictive test. The purpose of this research was to assess the attitudes, beliefs, and behavioral intentions concerning the impending predictive test by those at risk for HD. Results from a sample of 56 at-risk individuals indicated that a majority (65%) favored using the presymptomatic test and would encourage their adult children to use it as well. Fewer but still a substantial percentage of respondents would use the prenatal test (42%) and would test at-risk minors (35%). Surprisingly, knowledge about predictive testing was quite low and a majority of those least knowledgeable about predictive testing intended to use the test. These findings emphasized the need for outreach and prevention efforts to prepare the at risk and specialized programs of genetic counseling and follow up to accompany predictive testing.