Attitudes toward presymptomatic testing in Huntington disease

One hundred thirty-one individuals at 50% risk of inheriting Huntington disease (HD) responded to a survey to study their attitudes toward taking a genetic test based on the identification of a genetically linked DNA polymorphism. Ninety-six percent of the respondents believe that presymptomatic testing should be available, and 66% say they will use it themselves. Fewer married individuals, in comparison to those single, separated, and divorced, intend to take the test. Many respondents (40%) said their primary reason for wanting to be tested is to end the uncertainty in their lives. Results suggest that there will be self-selection in test use, with many individuals who believe they will be depressed or possibly suicidal with a positive test result deciding not to be tested or unsure about testing. However, 15% of those who want to be tested acknowledge that they may be at risk for suicide if they are probable gene carriers. Only 12% of all respondents say they will be likely to use prenatal testing, suggesting that initial demand may be low in New England. Implementation of presymptomatic testing challenges health care providers to develop strategies to care for otherwise healthy persons who will be given a diagnosis years before the onset of illness.     

Long-term outcome of presymptomatic testing in Huntington disease

Our study on long-term outcome of presymptomatic testing for Huntington disease had two aims: the comparison of the psychological well-being and social adjustment of carriers and non-carriers of the mutation, and the identification of psychological determinants to improve care/support of testees. We performed a cross-sectional study of 351 persons who underwent presymptomatic testing. Those who had motor signs were excluded from the comparison of asymptomatic carrier and non-carriers. A structured interview including five self-report scales and the MINI (Mini International Neuropsychiatric Inventory) was proposed to detect a psychopathology or problem with social adjustment.We interviewed 119 testees (53%), 62 non-carriers and 57 carriers after a mean delay of 3.7 years (range: 0.32 to 8.9) after their result. Depression was frequent in asymptomatic carriers (58%). Interestingly, the self reported impact of the test showed that 27% of non-carriers did not cope well with a favourable result, and a significant percentage of non-carriers (24%) were depressed during follow-up. Multivariate analysis showed that only a previous episode of depression was predictive of depression after genetic testing in both carriers and non-carriers of the HD mutation (P<0.0001).Psychological support is necessary for all testees regardless of the result of their presymptomatic test, because psychiatric care is often needed by both carriers and non-carriers.     

Long-term impact of Huntington disease linkage testing

We performed a long-term follow-up of Huntington disease (HD) predictive testing (an average of 6 years post-test) for 16 of 20 people who received informative linkage test results. Although no pre-test or baseline psychological differences were noted between those with an increased versus a decreased risk of HD, the long-term impact was dramatically different in these two groups. The low-risk group reported less uncertainty, anxiety or worry, fear, and worry about children's risk, whereas the high-risk group reported either the same or increased concern in these areas. Those at low risk also acknowledged an increased sense of control and self-esteem, whereas those at high risk reported decreases or no changes. One high-risk individual reported chronic depression that had occurred since the testing. Additionally, those at low risk reported greater reliance and faith in spiritual or religious beliefs than those at high risk. The emotional impact of HD genetic testing justifies the continued utilization of pre- and post-test counseling protocols. Pre-test counseling should include discussion of the known risks and benefits of predictive testing, with special emphasis on the participant's expectations for future change and improvement. Although the psychological impact appears mostly favorable for those with decreased risk, there is risk for a decline in psychological well-being over time for those with an increased risk for HD. Am J. Med. Genet. 70:365–370, 1997. © 1997 Wiley-Liss, Inc.     

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.     

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.     

Development of genomic reference materials for Huntington disease genetic testing

PurposeDiagnostic and predictive testing for Huntington disease requires an accurate measurement of CAG repeats in the HD (IT15) gene. However, precise repeat sizing can be technically challenging, and is complicated by the lack of quality control and reference materials (RM). The aim of this study was to characterize genomic DNA from 14 Huntington cell lines available from the National Institute of General Medical Sciences Human Genetic Cell Repository at the Coriell Cell Repositories for use as reference materials for CAG repeat sizing.MethodsFourteen Huntington cell lines were selected for study. The alleles in these materials represent a large range of sizes that include important diagnostic cutoffs and allele combinations. The allele measurement study was conducted by ten volunteer laboratories using a variety of polymerase chain reaction-based in-house developed methods and by DNA sequence analysis.ResultsThe Huntington alleles in the 14 genomic DNA samples range in size from 15 to 100 CAG repeats. There was good agreement among the ten laboratories, and thus, the 95% confidence interval was small for each measurement. The allele size determined by DNA sequence analysis agreed with the laboratory developed tests.ConclusionThese DNA materials, which are available from Coriell Cell Repositories, will facilitate accurate and reliable Huntington genetic testing.     

Impact of genetic testing for Huntington disease on the family system

The psychological impact of DNA predictive testing on asymptomatic individuals at risk for Huntington disease (HD) has received considerable attention since the advent of the procedure in 1993. This study examined the impact of such testing on families from the families' perspective. Individuals asymptomatic at the time of testing, together with their families, were interviewed in their homes with a semi-structured interview. Eighteen families with a total of 55 individuals participated. Defining the family as the unit of analysis was consistent with Systems Theory that links interactions of individuals, families, and the social environment. Areas of affected family functioning noted by the respondents included: 1) family membership; 2) family patterns of communication; and 3) future care giving concerns as they influenced current relationships. Eighty-one percent of families experienced changes in family membership. Members in 50% of families experienced changes in patterns of communication, and 56% percent of persons reported changes in current relationships in response to test results and their implications for future caregiving. The data support the conclusion that genetic testing is a family, as opposed to an individual, matter and that family involvement in the decision making process should be strongly encouraged in order to help families adjust. The data imply that families will benefit in pre-test sessions from an examination of their patterns of dealing with illness issues, both past and present.     

Polymorphisms in the CAG repeat--a source of error in Huntington disease DNA testing

Five of 400 patients (1.3%), referred for Huntington disease DNA testing, demonstrated a single allele on CAG alone, but two alleles when the CAG + CCG repeats were measured. The PCR assay failed to detect one allele in the CAG alone assay because of single-base silent polymorphisms in the penultimate or the last CAG repeat. The region around and within the CAG repeat sequence in the Huntington disease gene is a hot-spot for DNA polymorphisms, which can occur in up to 1% of subjects tested for Huntington disease. These polymorphisms may interfere with amplification by PCR, and so have the potential to produce a diagnostic error.     

Psychosocial impact of predictive testing for Huntington disease on support persons

Although a support person is required by many centers during the predictive testing protocol for Huntington disease (HD), little is known about the psychosocial impact of predictive testing on persons serving in this role. Eighteen adults who were support persons during predictive HD testing in one HD testing center completed a semi-structured interview to describe their experiences. Participants also completed the Impact of Events Scale (IES) to assess perceptions of emotional distress regarding predictive testing and the State Anxiety Scale of the State Trait Anxiety Inventory (STAI) to assess anxiety regarding the interview. State anxiety scores were similar to normative values for working adults. Although support persons for individuals with a positive gene test scored higher on all measures of the IES than those who were support persons for persons with negative gene mutation results, these differences were not statistically significant. Support persons identified aspects of the protocol that did not fit their needs, perceived the testing process as extending into subsequent caregiving responsibilities when the test was positive, and were uninformed regarding specific caregiving issues for family members with the gene mutation. The impact of the testing experience appeared to be most intense for those support persons who were at-risk offspring of probands. Findings suggest that individual assessment of support person needs may allow more focused counseling of support persons during predictive genetic HD testing. Collaboration with health care providers may facilitate symptom management following testing.     

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.     

Prenatal exclusion testing for Huntington disease using the polymerase chain reaction

Prenatal exclusion of Huntington disease (HD) may be carried out by analysis of cosegregating DNA markers on a first-trimester chorionic villus sample. The conventional Southern blot method is time-consuming and requires microgram quantities of DNA and milligram quantities of villus tissue. The use of the polymerase chain reaction (PCR) to amplify genomic DNA by a factor of 10(7) or more makes it possible to do analyses on very small samples in a few hours and without recourse to Southern blotting or hybridization with radioactive probes. We report on a fetus at risk of HD; prenatal testing was carried out by using the PCR to amplify a polymorphic DNA sequence adjacent to the HD locus. The risk of the fetus inheriting the HD gene could not be excluded and the pregnancy was terminated. This represents an example of gene tracking by using amplification of a restriction fragment length polymorphism at some distance from the relevant mutation.     

At-risk persons' attitudes toward presymptomatic and prenatal testing of Huntington disease in Michigan

One hundred fifty-five individuals at 50% risk of inheriting Huntington disease (HD) were given a questionnaire surveying their sociodemographic characteristics, experience with HD, and attitudes toward presymptomatic and prenatal testing in HD. About two-thirds (63.2%) of the persons indicated they would take a presymptomatic test even if no specific treatment was available. Although one-half (49%) of the respondents stated they would make use of a prenatal test, only 43% of these individuals would decide to terminate a heterozygous fetus. Presymptomatic test results indicating carrier status would influence some of the respondents' decisions about marriage and childbearing. This strong interest of at-risk persons to make use of both presymptomatic and prenatal diagnosis in HD indicates the need for well-organized testing programs. These programs must be designed to address the genetic, psychosocial, and ethical issues that may arise in the use of this type of genetic test.     

Problems assessing uptake of Huntington disease predictive testing and a proposed solution

The uptake of predictive testing for Huntington disease informs our understanding of decision making by those at risk and assists with planning for service provision. Uptake figures have been reported from several centers based on the total number of people who have undertaken predictive testing as a percentage of those estimated to be at 50% risk in the region. This method produced a figure of 35% from our own service, much higher than observation of the local pedigrees indicated, and higher than other published reports. We have identified some errors in the commonly used formula. The major errors are the use of the cumulative total of those who have had testing with a static denominator of those at 50% risk, and the failure to exclude from the at-risk group those who are too young and therefore ineligible to test.We report data from the Huntington Disease Register of Victoria and estimate the prevalence to be 8 per 100,000 in 1999. Additional data on individuals at risk were collated. We found that for every diagnosed person there were 4.2 individuals at 50% risk, a lower ratio than one to five hypothesized in the literature. We examined these ratios in the context of uptake.Significantly, we provide a solution to the calculation of uptake with a formula that factors in a dynamic denominator and corrects for the number of years testing has been offered. Using this formula, we calculated an uptake of 13.0-15.4% for the state of Victoria, Australia. This formula can be used to compare uptake across different centers.     

Preimplantation genetic testing for Huntington disease and certain other dominantly inherited disorders

Preimplantation genetic testing (PGT) on embryos from couples at risk for Huntington disease can achieve disease prevention in offspring without disclosure of parental genotype. This strategy may also be applicable to other extremely deleterious dominant traits.     

Predictive testing for Huntington disease: interpretation and significance of intermediate alleles

Direct mutation analysis for Huntington disease (HD) became possible in 1993 with the identification of an expanded CAG trinucleotide repeat as the mutation underlying the disease. Expansion of CAG length beyond 35 repeats may be associated with the clinical presentation of HD. HD has never been seen in a person with a CAG size of <36 repeats. Intermediate alleles are defined as being below the affected CAG range but have the potential to expand to >35 CAG repeats within one generation. Thus, children of intermediate allele carriers have a low risk of developing HD. Currently, the intermediate allele range for HD is between 27 and 35 CAG repeats. In this study, we review the current knowledge on intermediate alleles for HD including the CAG repeat range, the intermediate allele frequency, and the clinical implications of an intermediate allele predictive test result. The factors influencing CAG repeat expansion, including the CAG size of the intermediate allele, the sex and age of the transmitting parent, the family history, and the HD gene sequence and haplotype, will also be reviewed.     

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.     

Phenotypic heterogeneity in Huntington disease

Two Huntington disease (HD) pedigrees are presented which differ according to mean and distribution of the age at onset, the effect of paternal transmission on the age at onset, presence of manic-depressive symptoms, and type of presenting symptoms. Together with previous reports, the data suggest clinical heterogeneity between HD kindreds which may imply some kind of genetic heterogeneity, most likely subsequent mutation at a single HD locus. The possibility of genetic heterogeneity has important consequences, both in research, and in the counseling and care of families and patients with differing manifestations of the disease.