Predictive,pre-natal and diagnostic genetic testing for Huntington's disease: the experience in Canada from 1987 to 2000

Predictive and pre-natal testing for Huntington's Disease (HD) has been available since 1987. Initially this was offered by linkage analysis, which was surpassed by the advent of the direct mutation test for HD in 1993. Direct mutation analysis provided an accurate test that not only enhanced predictive and pre-natal testing, but also permitted the diagnostic testing of symptomatic individuals. The objective of this study was to investigate the uptake, utilization, and outcome of predictive, pre-natal and diagnostic testing in Canada from 1987 to April 1, 2000. A retrospective design was used; all Canadian medical genetics centres and their affiliated laboratories offering genetic testing for HD were invited to participate. A total of 15 of 22 centres (68.2%), currently offering or ever having offered genetic testing for HD, responded, providing data on test results, demographics, and clinical history. A total of 1061 predictive tests, 15 pre-natal tests, and 626 diagnostic tests were performed. The uptake for predictive testing was approximately 18% of the estimated at-risk Canadian population, ranging from 12.5% in the Maritimes to 20.7% in British Columbia. There appears to have been a decline in the rate of testing in recent years. Of the predictive tests, 45.0% of individuals were found to have an increased risk, and a preponderance of females (60.2%) sought testing. A greater proportion of those at < or = 25% risk sought predictive testing once direct CAG mutation analysis had become available (10.9% after mutation analysis vs 4.7% before mutation analysis, p = 0.0077). Very few pre-natal tests were requested. Of the 15 pre-natal tests, 12 had an increased risk, resulting in termination of pregnancy in all but one. Diagnostic testing identified 68.5% of individuals to be positive by mutation analysis, while 31.5% of those with HD-like symptoms were not found to have the HD mutation. The positive diagnostic tests included 24.5% of individuals with no known prior family history of HD.     

Impact on couple relationships of predictive testing for Huntington disease: a longitudinal study

Since predictive testing has been available for Huntington disease (HD) and similar adult-onset neurodegenerative disorders, research into the psychosocial impact of test results has focussed on those receiving results, and to a lesser extent, on their partners. Few studies have examined the impact of predictive testing on the couple relationship, particularly from the perspective of family systems theory. This longitudinal study compared the level of marital adjustment of 23 couples in which the at-risk partner is undergoing predictive testing for HD (the testing group) with that of 20 couples in which the at-risk partner is not undergoing testing (the non-testing group). Participating couples completed a relationship measure, the Dyadic Adjustment Scale, at baseline and on two subsequent occasions. Using non-parametric tests, comparisons were made at each phase between the couple scores of the testing and non-testing groups but no significant differences were found in the levels of marital adjustment. Within the testing group the same comparisons were made for the carrier and non-carrier subgroups, and a significant difference was found at the final phase. There was an increase in the level of marital adjustment for the carrier group and a decrease for the non-carrier group. Together with trends observed in the data, this finding suggests a need for greater attention to be given to the potential impact of predictive testing on the couple relationship. Offering couples pre-result relationship assessment and referral for couple therapy, if warranted, may enhance the quality of professional support during the predictive testing process.     

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.     

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.     

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.     

Anthropometric discrimination among affected, at-risk, and not-at-risk individuals in families with Huntington disease

An earlier report showed significant differences among Huntington disease (HD) patients, controls, and particular age cohorts of at-risk persons for several dimensions of body mass and for several linear and craniofacial components of the body. In this investigation a function was derived from a stepwise discriminant analysis of the affected and unaffected groups, and used to classify the at-risk individuals according to HD gene carrier status. The function, comprised of body mass index, subscapular skinfold, head length, and sitting height, classified 95% of the controls and 87% of the affected individuals correctly. Approximately 80% of the individuals at-risk were classified with 80% or greater certainty. We propose that anthropometric variables may prove to be a powerful tool for basic research in HD and the derived discriminant function has potential clinical value as a diagnostic and preclinical diagnostic aid. We emphasize that corroborative testing on other sample populations of HD families is required before these techniques are utilized. Also, it is imperative that the anthropometric protocol include appropriate standardization of the raw measurement data.     

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.     

Predictive testing for Huntington disease: I. Description of a pilot project in British Columbia

The discovery of DNA markers linked to the gene causing Huntington disease (HD) has allowed the development of predictive testing programs for persons at-risk. A pilot program was established in British Columbia in November 1986. Ninety-five persons are currently enrolled. The major objective of this project is to introduce and evaluate a protocol for the delivery of test results to persons at-risk for HD. The criteria for entry and details of the psychosocial assessment before and after receiving a modified risk are presented. The guidelines that are developed from this project will have major applications for predictive testing programs for other late onset autosomal dominant disorders.     

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.     

New tools for preimplantation genetic diagnosis of Huntington's disease and their clinical applications

Huntington's disease (HD) is a late-onset neurodegenerative disorder transmitted as an autosomal dominant trait. The causative mutation was characterised in 1993. For HD carriers willing to create a family, prenatal diagnosis (PND) or preimplantation genetic diagnosis (PGD) based on the mutation identification can be offered. For at-risk persons who do not want to undergo presymptomatic testing (PT), an exclusion test can be proposed. With such a test, only foetuses or embryos that inherit an allele from the unaffected grandparent are considered as unaffected. In cases of PND, if the foetus has one allele of the affected grandparent, termination of pregnancy is proposed. In cases of PGD, only not at-risk embryos are transferred. Since the beginning of our PGD activity, we have had 43 PGD referrals for HD, of which 24 were from patients who know their genetic status and 19 from patients who do not wish to perform PT. We have developed 12 multiplex fluorescent PCR protocols applied at the single-cell level for PGD, some of which target the CAG repeat while others use two different polymorphic microsatellites. We present here these different protocols and their clinical applications, as well as the characterisation and use of a new highly polymorphic intragenic marker. Between May 2001 and December 2003, 39 PGD cycles have been performed for 17 couples, 11 of whom had a known genetic status and six who did not wish to perform PT, resulting in four pregnancies.     

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.     

Huntington's disease in Greece: the experience of 14 years

A large scale genetic and epidemiological study of Huntington's disease (HD) was carried out in Greece from January 1995 to December 2008. Diagnostic testing was carried out in 461 symptomatic individuals, while 256 were tested for presymptomatic purposes. The diagnosis of HD with a CAG expansion ≥ 36 was confirmed in 278 symptomatic individuals. The prevalence of HD in Greece was estimated at approximately 2.5 to 5.4:100,000, while the mean minimum incidence was estimated at 2.2 to 4.4 per million per year. The molecular diagnosis of HD was confirmed in the majority of patients (84.4%) sent for confirmation. The false-positive cases 15.6% were characterized by the absence of a family history of HD and the presence of an atypical clinical picture. The uptake of predictive testing for HD was 8.6%. A prenatal test was requested in six pregnancies. The findings of our study do not differ significantly from those of similar studies from other European countries despite the relative genetic isolation of Greece. Of interest is the identification of clusters of HD in Greece. The presence or absence of a family history of HD should be interpreted cautiously, during the diagnostic process.     

Suicide and attempted suicide in Huntington disease: implications for preclinical testing of persons at risk

Suicide behavior in Huntington disease (HD) was assessed by examining the proportion of deaths attributed to suicide among 452 deceased individuals with HD and the number and pattern of attempted suicides among a total population of 831 HD patients from the National Huntington Disease Research Roster. It was found that 5.7% of deaths among affected persons resulted from suicide and 27.6% of patients attempted suicide at least once. Comparison of this group with the general population indicated that the proportion of deaths due to suicide among persons with HD is almost four times greater than the corresponding proportion for the U.S. Caucasian population. Age at onset of HD was not significantly different between HD suicide and non-suicide patients, although suicide occurred more frequently in the early to middle stages of the illness. The "success" rate among HD suicide attempters did not differ from the general population rates in several western European countries. The relatively high suicide and attempted suicide rates in HD indicate that thorough psychological testing of at-risk persons and extensive patient support systems must be integral components of a program to identify HD gene carriers using a genetic marker.     

Epidemiology of Huntington disease in Cyprus: A 20‐year retrospective study

Huntington disease (HD) is most prevalent among populations of western European descent and isolated populations where founder effects may operate. The aim of this study was to examine the epidemiology of HD in Cyprus, an island in southern Europe with extensive western European colonization in the past. All registered HD patients in the Cyprus, since 1994, were included. Detailed pedigrees and clinical information were recorded and maps, showing the geographic distribution of HD, were constructed. Requests for genetic testing were also examined. The project identified 58 clinically manifested cases of HD belonging to 19 families. The 16 families of Cypriot origin were concentrated in a confined geographical cluster in southeast Cyprus. In 2015, prevalence of symptomatic HD was 4.64/100 000 population, while incidence was 0.12/100 000 person‐years . Prevalence displayed a marked increase during the past 20 years. Disease characteristics of HD patients were similar to those reported in western European populations. Lastly, the uptake of predictive and/or prenatal testing was limited. HD disease characteristics, incidence and prevalence in Cyprus were comparable to western European populations. Together with the geographical clustering observed, these results support the possibility for a relatively recent founder effect of HD in Cyprus, potentially of western European origin.     

A pilot assessment of parental practices and attitudes regarding risk disclosure and clinical research involving children in Huntington disease families

PurposeTo characterize parental practices of informing children of risk for Huntington disease (HD), and to understand the attitudes of parents concerning childhood participation in HD research.MethodsAn anonymous Internet survey was accessed by individuals of HD families. The survey probed for data regarding individual risk for HD, as well as when or if children had been informed of the disease. Respondents expressed their attitudes concerning childhood participation in HD clinical research.ResultsTwo hundred forty-nine individuals responded (∼80% female), and 84% had never participated in an HD clinical trial. Seventy-five percent of respondents were parents; nearly two thirds of them had provided some information about HD to their children. There was overwhelming support for affected, at-risk, and unaffected adults in terms of HD research participation, but there was a statistically significant disparity by gene status, with gene negative and symptomatic gene positive adults being more inclined to participate than at-risk or asymptomatic/gene positive adults. More than 50% of respondents supported childhood participation, but typically in late adolescence (15–18 years). Gene negative and symptomatic adults were statistically more likely to agree with childhood inclusion than at-risk or asymptomatic/gene positive adults.ConclusionThese results serve as pilot data for further investigations to address childhood participation in HD research. In addition, these findings will inform ongoing studies as to appropriate practices to undertake to include minors.     

Predictive testing for Huntington's disease: II. Qualitative findings from a study of uptake in South Wales

Semi-structured interviews were conducted with a cohort of 22 test applicants who requested Huntington's disease (HD) predictive testing in South Wales, and a random sample of 32 non-requesters, drawn from the South Wales HD register. Apart from identifying differences between the groups, the study afforded the opportunity to listen, at length, to at-risk individuals' accounts of living at risk and their thoughts about predictive testing and genetic services. Emergent themes included difficulties in family communication and the uncertainties inherent in being at risk and undergoing testing. Important factors in decision making about testing were: moral imperatives to clarify one's genetic status; views about the controllability of the future; family attitudes and norms; and the impact of a test result on family members. At-risk individuals' perceptions of the genetics service were that contact with the service would result in pressure to be tested and a need for test applicants to present a favourable view of coping capacities to secure testing. In addition, there was an expectation of ongoing contact with HD families at the initiative of the service providers. Implications of the findings for the way in which predictive testing services are structured and introduced to the at-risk population are discussed.     

Electrodermal Activity in Patients with Huntington''s Disease and Their Progeny

Skin conductance was examined in patients with Huntington's disease (HD) and progeny at risk for HD to determine if electrodermal characteristics had potential to identify those progeny likely to succumb to HD. The two experimental groups chosen for study consisted of 7 patients in the early stages of HD and 29 progeny of HD patients. Because the HD and at-risk groups differed in age and sexual composition, each was matched by age and sex to separate psychiatrically and medically healthy normal control samples. Skin conductance was recorded bilaterally while subjects listened to three series of stimuli: 8 85dB tones, 12 105dB tones, and two familiar sounds. Dependent measures included skin conductance level, number of nonspecific responses, number of responses elicited by each tone series and the sounds, the amplitude, latency, rise time, and half-recovery rime of the first tone-elicited response in each series, and habituation rate to the soft and loud tones. The data analysis was carried out by comparing each experimental group to its matched comparison sample. A variety of parametric and nonparametric tests were carried out; no significant differences emerged either between the HD patients and their control group or between the at-risk subjects and their normal comparison group. Ninety-seven percent and 86% of the at-risk and HD subjects, respectively, responded at least once to the experimental stimuli, compared to 90% and 86% of the corresponding control groups.     

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.