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PubMed2005

Genotype-based screening for hereditary hemochromatosis: II. Attitudes toward genetic testing and psychosocial impact--a report from a German pilot study.

In collaboration with the German Sickness Fund (Kaufmännische Krankenkasse-KKH), we conducted a pilot study on DNA-based population screening of hereditary hemochromatosis (HH) in Germany. The health insurance organization KKH briefly informed their members about the possibility to participate voluntarily in this pilot project. A total of 5882 KKH members contacted us and received detailed information on the aim of the project and clinical and genetic aspects of HH. Of these individuals, 3961 requested HFE genotyping. After genotype results had been communicated to the participants' general practitioner, we sent a self-administered questionnaire to all homozygous (n = 67) and heterozygous (n = 485) as well as 448 wild-type study participants (sigma = 1000) to assess the psychosocial impact of HFE genotyping. In addition, questionnaires were sent to 8000 randomly selected members of the KKH to investigate their attitude toward genetic testing. Six hundred thirty-one (63.1%) of the test participants and 2141 (26.8%) of the randomly chosen KKH members responded. A total of 59.1% of the members would generally accept predictive genetic testing and 3.7% objected to such tests in principle. Individuals with higher educational status accepted predictive testing significantly more often than individuals with less education. Of the tested individuals, 69.9% thought that participation in the pilot study was probably beneficial for them and 1% (5 heterozygotes and 1 wild-type) thought that it was probably harmful. Of the participants, 94.6% judged their decision to have participated in the pilot study as right and 0.3% (2 heterozygotes) as probably wrong. Only very few of the tested individuals underwent pretest (1 case) or posttest (11 cases) genetic counseling. We conclude that genotype- based screening for HH is generally accepted and was perceived as beneficial. Negative psychosocial consequences are rare and could presumably have been prevented by delivering appropriate pretest and posttest information.

Attitude↗
PubMed2002

[Predictive genetic testing - change in paradigms for prevention and health care?].

The post-genomic era promises to offer new insights into the nature of disease, its prevention, and treatment. But now that there is a draft code of the human genome, what does this knowledge mean and how might it be applied? How to use genetic information to promote health and prevent disease - the fundamental mission of public health - will be one of the most challenging tasks in future. Assessing the benefits and risks of predictive genetic testing and the efficacy of early interventions as well as exploring complex issues that have emerged (e. g., rapid commercialization of genetic tests, availability of and access to interventions, and potencial discrimination) call for public health leadership.

Forecasting↗
PubMed2004

Genetic testing for cardiovascular disease susceptibility: a useful clinical management tool or possible misinformation?

Genetic susceptibility tests are already advertised on the Internet to identify individuals at above average risk for cardiovascular disease (CVD), such as deep vein thrombosis, hyperlipidemia, or atherosclerosis, whereas other tests claim to predict response to a particular drug treatment. Some kits are available to the public directly, bypassing a doctor. Their value, however, must be considered carefully, because although a genotype may be strongly and consistently associated with an intermediate trait, and because the intermediate trait is a strong predictor of CVD risk, there may be little or no association of genotype with risk over and above that of the measured trait. This is because multigenic effects and environmental modification (context dependency) of genotype effects determine CVD risk. An individual's personal characteristics and plasma risk-trait levels (which reflect both genotype and exposure) at present are the best predictors of clinical outcome. Only when genetic tests surpass this, possibly by the inclusion of many functional common variants, in conjunction with their context-dependent effects on risk, might their usefulness in clinical management be realized. Here we review some of the particular issues and concerns raised by CVD-risk genetic testing, and suggest areas of further research to address these issues.

Apolipoproteins E↗
PubMed2006

Late-onset medullary carcinoma of the thyroid: need for genetic testing and prophylactic thyroidectomy in adult family members.

OBJECTIVE: Sporadic late-onset medullary carcinoma of the thyroid is quite rare. Usually, the patient presents with a thyroid mass or neck node metastasis along with high levels of calcitonin and preoperative fine needle aspiration biopsy suggestive of medullary carcinoma of the thyroid. The role of genetic testing in such individuals, along with testing of other family members, remains somewhat unclear at this stage, especially in patients presenting with familial medullary thyroid carcinoma. Genetic testing with RET proto-oncogene mutational studies is very popular in familial medullary thyroid carcinoma, especially in children, with routine prophylactic thyroidectomy. However, its indications in adults remain unclear at this time. CASE STUDY: Recently, a 69-year-old woman presented with a thyroid mass and underwent total thyroidectomy and central compartment dissection. She was found to have medullary carcinoma of the thyroid. The patient had four children, three of whom were found to have a RET mutation similar to their mother's, V804M. In view of the RET mutation, the three children were offered prophylactic thyroidectomy at ages 42, 45, and 47. The patient's son was noted to have extensive C-cell hyperplasia in both lobes of the thyroid. The other two individuals had benign pathology with no evidence of C-cell hyperplasia. CONCLUSIONS: There is no definite consensus of opinion about the need for prophylactic total thyroidectomy in adults with RET mutation. The rarely reported 804 mutation is, however, a predictor of medullary carcinoma of the thyroid. One individual in this group had extensive C-cell hyperplasia, suggesting that he would have developed medullary carcinoma of the thyroid in the future. Prophylactic thyroidectomy should be recommended in patients with RET mutation and a family history of medullary carcinoma of the thyroid; however, its role in adult family members needs to be evaluated with larger registry of prophylactic thyroidectomy. Whether these adults with rare 804-mutation could be observed and followed with serial calcitonin, ultrasound, or calcitonin stimulation tests remains to be studied.

Adult↗
PubMed2005

Spectrum and prevalence of cardiac ryanodine receptor (RyR2) mutations in a cohort of unrelated patients referred explicitly for long QT syndrome genetic testing.

BACKGROUND: Mutations in the RyR2-encoded cardiac ryanodine receptor/calcium release channel cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1). OBJECTIVES: Because CPVT and concealed long QT syndrome (LQTS) phenotypically mimic one other, we sought to determine the spectrum and prevalence of RyR2 mutations in a cohort of unrelated patients who were referred specifically for LQTS genetic testing. METHODS: Using denaturing high-performance liquid chromatography and direct DNA sequencing, targeted mutational analysis of 23 RyR2 exons previously implicated in CPVT1 was performed on genomic DNA from 269 unrelated patients (180 females, average age at diagnosis 24 +/- 17 years) who were referred to Mayo Clinic's Sudden Death Genomics Laboratory for LQTS genetic testing. Previously, comprehensive mutational analysis of the five LQTS-associated cardiac channel genes proved negative for this entire subset of patients now designated as "genotype-negative" LQTS referrals. RESULTS: Fifteen distinct RyR2 mutations (14 missense, 1 duplication/insertion, 12 novel) were found in 17 (6.3%) of 269 patients. None of these mutations were present in 400 reference alleles. Two mutations localized to the calstabin-2 (FKBP12.6) binding domain. Upon review of the clinical records, the referral diagnosis for all 17 patients was "atypical" or "borderline" LQTS. CONCLUSION: Putative pathogenic CPVT1-causing mutations in RyR2 were detected in 6% of unrelated, genotype-negative LQTS referrals. These findings suggest that CPVT may be underrecognized among physicians referring patients because of a suspected channelopathy. A diagnosis of "atypical LQTS" may warrant consideration of CPVT and analysis of RyR2 if the standard cardiac channel gene screen for LQTS is negative.

Adolescent↗
PubMed2002

Attitudes toward genetic testing in patients at risk for HNPCC/FAP and the German population.

Adequate knowledge regarding hereditary diseases and genetics, as well as personal attitudes toward gene tests, are major determinants of optimal utilization of genetic testing. In the present study, we aimed to explore the general attitudes toward genetic testing in a sample representative of the German general population (n = 2,076) and to compare the attitudes of persons at risk for hereditary non-polyposis colorectal cancer/familial adenomatous polyposis (HNPCC/FAP) (n = 36) who had attended a university genetic counseling service, with a matched general population sample. We administered a subset of a questionnaire previously used in a Finnish study (Jallinoja et al., 1998). The 12 statements pertain to approval, disapproval, and concern for genetic testing. Overall, the results reveal high approval of genetic testing in the German population and in at-risk persons. In accordance with other studies, we find that the attitudes of individuals for whom hereditary disease is a salient issue of personal relevance and the attitudes of the general public are very similar. Only a few significant differences between these two samples emerged, indicating that at-risk persons hold a more favourable view of the testing. One intriguing finding was the high rate of "don't know" responses, especially in the general population sample. Compared to results from Finland, approval of genetic testing is lower in the German population, and endorsement of "don't knows" is remarkably higher. We argue for increased attention to the issue of attitude change after genetic counseling and for the need of comparative cross-cultural research on attitudes toward gene technology.

Adenomatous Polyposis Coli↗
PubMedDate not supplied

Predictive genetics in primary care: expectations for the motivational impact of genetic testing affects the importance family physicians place on screening for familial cancer risk.

PURPOSE: To investigate whether the importance family physicians place on familial cancer-risk screening is influenced by expectations for the motivational impact of a high-risk genetic test result. METHODS: Mailed survey of the Massachusetts Academy of Family Physicians. RESULTS: Respondents expected patients would increase pursuit of screening for cancer (99.6%) and other diseases (89.9%), quit smoking (93.6%), and improve diet/exercise (92.5%). The degree of motivational effect was significantly related to the importance they place on screening. CONCLUSIONS: Family physicians believe that a high-risk cancer genetic-test result would motivate their patients to pursue risk-reduction behavior, and this belief is related to the importance they place on screening their patients for an inherited risk of cancer.

Attitude of Health Personnel↗
PubMed2003

Genetic testing in chronic pancreatitis.

Genetic changes associated with some forms of chronic pancreatitis have been recently defined. There are three genes that play a role, each with a variety of genotypes and different pathologic mechanisms and clinical correlations. Selection of the appropriate diagnostic tests requires integration of the clinical and family history and the interpretation of results has a significant impact on genetic counseling for the patient and family. The relative significance of some variant alleles is still under investigation as they are common in the population and show low penetrance. Knowledge of the pathophysiology of each abnormal allele could lead the way towards more specific therapeutic options in the future.

Chronic Disease↗
PubMed2003

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.

Adolescent↗
PubMed1993

Confidentiality in genetic testing: legal and ethical issues in an international context.

This comparative legal study on confidentiality in genetic testing examines three levels of communication of genetic information: the personal; the familial; and the institutional third parties. At the first two levels, it is argued that the approach is one that recognizes genetic individuality and reciprocity within the physician-patient relationship without legislative interference. This stands in contrast to the possible use of genetic information by economic third parties or, even, that of the state with respect to the DNA profiling of the genetic identity of criminals, the approach for both areas being the promulgation of 'genetic-specific' or human rights legislation with the hope of preventing discrimination. This rush to constrain the impact of genetic information through legislation is criticized since it may well lead to further stigmatization. The author proposes the promotion of the concept of genetic privacy within the broader rubric of informational self-determination.

Confidentiality↗
PubMed1998

Occurrence of MEN 2a in familial Hirschsprung's disease: a new indication for genetic testing of the RET proto-oncogene.

PURPOSE: The association of the rare hereditary cancer syndrome, multiple endocrine neoplasia type 2a (MEN 2a) with Hirschsprung's disease, both linked to germline mutations in the RET proto-oncogene, has been reported recently. With the widespread availability of genetic screening for MEN 2a, it is necessary to define the indications for genetic testing of MEN 2a and population subgroups at high risk for inheriting the disease. The purpose of this study was to assess the prevalence of Hirschsprung's disease in MEN 2a and investigate the value of genetic analysis for MEN 2a in children with familial Hirschsprung's disease. METHODS: The ethnically diverse study group consisted of unselected consecutive patients (n=426) at risk for hereditary medullary thyroid cancer (MTC) referred to a single laboratory for genetic testing. Analysis used genomic DNA and a polymerase chain reaction-based heteroduplex mutation detection strategy for exons 10, 11, 13, and 14 of the RET proto-oncogene followed by direct DNA sequencing. Significance of RET genotype-phenotype correlation was determined by Fisher's two-tailed Exact test and a 2 x 2 contingency table. RESULTS: Thirty-six distinctly new MEN 2a kindreds were identified. Hirschsprung's disease cosegregated among siblings with MEN 2a in 15 patients from 6 of the 36 (17%) families. The extent of aganglionosis in the 15 patients ranged from midrectum to duodenum. Of the 15 patients with Hirschsprung's disease, 10 (six boys, four girls) underwent thyroidectomy for MTC (n=5) or C-cell hyperplasia (n = 5) at ages 2 to 47 years (mean, 15.6 years), and the remaining five patients died in childhood of complications related to the aganglionosis. In retrospect, Hirschsprung's disease was the presenting feature of MEN 2a in five of the six families rather than MTC or pheochromocytoma. In all six MEN 2a families expressing Hirschsprung's disease, the RET mutation predisposing to the combined phenotype occurred in exon 10 at codons 609 (n=2), 618 (n=3), or 620 (n = 1). By contrast, the MEN 2a with Hirschsprung's phenotype was not found in any of the 22 families with a RETexon 11, 13, or 14 mutation (P=.0007). CONCLUSIONS: The authors conclude that Hirschsprung's disease is a phenotypic marker for MEN 2a and possibly more common than originally appreciated. The expression of Hirschsprung's disease with MEN 2a may be uniquely linked to RETexon 10 mutations. The authors recommend that (1) patients affected with MEN 2a may be counseled regarding the potential risk of Hirschsprung's disease in offspring and (2) a family history of MTC be explored in children with familial Hirschsprung's disease and genetic screening for MEN 2a be considered.

Adolescent↗
PubMed2006

[Attitudes towards predictive genetic testing for Alzheimer's disease].

Most neuropsychiatric disorders have a complex aetiology. Discovery of the underlying genetics will provide insights into the disorders and allow the subsequent development of therapeutic interventions based upon an understanding of causality. The first vulnerability genes in Alzheimer's disease (AD) have been identified. The contribution of each vulnerability gene to the disorder is limited and does not enable prediction of course and onset in individual cases, only modification of the a priori risk. However, people may wish to be informed about this modification. Professionals have not favoured this form of predictive testing due to an awareness of its limitations and its potential for harm. However, little is known about public attitudes and understanding of such genetic testing in neuropsychiatric disorders. The aim of our study was to assess the attitudes of the general population and to explore the influence on these attitudes of knowledge about the illness and the understanding of risk information. In our study, a representative sample of the German general population (n=2001), relatives of patients with Alzheimer's disease (n=101) and physicians (n=43) were interviewed about their attitudes towards genetic tests for Alzheimer's disease and their perception and interpretation of risk information. To assess the influence of genetic counselling on these factors, 234 people were questioned before, and four weeks after, they were provided with detailed relevant information. Our results indicate that a substantial proportion of the German population (57%) is in favour of psychiatric genetic testing for AD in general. Even when the explanatory power of a genetic test is limited, a substantial proportion of the population (47%) expressed an interest in genetic testing. Counselling slightly decreased the interest in having a genetic test for oneself (from 47% to 38%). Physicians were more hesitant than both relatives and the general population concerning predictive genetic testing. Only a minority (11%) favoured prenatal genetic testing. Our results also show that both knowledge about AD and the capacity to interpret risk estimates are limited. While physicians' estimation of their personal risk for developing AD approximated to the actual average risk for the population, people in the general population and the relatives of AD patients tended to overestimate their personal risk. However, most of the general population still perceived this risk as average or low. While most physicians could correctly interpret information regarding the probability of risk, only one third of AD patients' relatives or members of the general population could. As the decision of an individual to undergo predictive testing relies mainly on his understanding of risk, the ability to correctly interpret risk information will be of crucial importance in the future. From a medical perspective, the prevailing approach of professional associations to genetic testing appears reasonable and therefore should not be changed at present.

Adult↗
PubMed2003

Between acculturation and ambivalence: knowledge of genetics and attitudes towards genetic testing in a consanguineous bedouin community.

UNLABELLED: The Bedouins of the Negev (Southern part of Israel) are a community at increased risk for genetic diseases and congenital anomalies as a result of frequent consanguinity (particularly patrilateral parallel-cousin marriage) and underutilization of prenatal genetic tests due to a Muslim ban on abortion. OBJECTIVE: To assess the knowledge and attitudes of Bedouin schoolchildren and their teachers towards a community-based, premarital carrier-matching program aimed at reducing the prevalence at birth of genetic diseases. METHODS: A questionnaire was presented to 61 teachers and 40 schoolchildren as part of guided interaction in small groups, conducted in Bedouin schools between 1999 and 2001. RESULTS: Susceptibility as well as knowledge of genetics were found to correlate with a positive attitude towards the genetics program among both teachers and pupils. However, pupils had a lower knowledge index as compared to teachers, and their attitudes were slightly less positive. CONCLUSION: The difference between teachers and pupils is discussed in the context of the latter's acculturation, which contradicts tradition and parental authority and can generate ambivalence. Attitudes are further discussed in the context of the Health Belief Model and the complex interplay of tradition, Islam, cousin marriage and biomedicine.

Acculturation↗
PubMed2006

Assessing risk assessment: genetic testing and screening for complex disease.

This paper reports on the presentations from the second session of a 2-day workshop on genetic diversity and science communication, organized by the Institute of Genetics. The four talks in this session (by Sarah Cunningham-Burley, Gail Geller, Michael Hayden, and Theresa Marteau) focused on the topic of risk assessment in the context of genetic testing, screening and preventive medicine for complex disease. Each talk underscored the urgency and importance of evaluating when and for whom risk assessment may be useful. A recurrent theme was the need to attend closely to the diverse ways that risk is constructed, perceived and communicated in a variety of contexts and the significant implications of this for laypersons as well as experts. Although there was no consensus on when genetic risk assessment ceases (or might begin) to be useful, ensuing dialogue between presenters and participants reflected what is perhaps a new and critical engagement with how risk assessment itself is assessed. In response to this impetus, I use the word RISK as a heuristic to identify, extract and amplify four tendencies that appear to advance understandings of risk assessment towards a more explicitly reflexive, interpretive, and situated form of knowing.

Communication↗
PubMed2006

Morphology of breast cancer as a means of triage of patients for BRCA1 genetic testing.

BACKGROUND: Women who have germline mutations in the BRCA1 gene are at substantially increased lifetime risk of developing breast and ovarian cancer but are otherwise normal. Currently, early age of onset of cancer and a strong family history are relied upon as the chief clues as to who should be offered genetic testing. Certain morphologic and immunohistochemical features are overrepresented in BRCA1-associated breast cancers but these differences have not been incorporated into the current selection criteria for genetic testing. DESIGN: Each of the 4 pathologists studied 30 known cases of BRCA1- and BRCA2-associated breast cancer from kConFab families. After reviewing the literature, we agreed on a semiquantitative scoring system for estimating the chances of presence of an underlying BRCA1 mutation, based on the number of the reported prototypic features present. After a time lag of 12 months, we each examined a series of 62 deidentified cases of breast cancer, inclusive of cases of BRCA1-associated breast cancer and controls. The controls included cases of BRCA2-associated breast cancer and sporadic cases. RESULTS: Our predictions had a sensitivity of 92%, specificity of 86%, positive predictive value of 61%, and negative predictive value of 98%. For comparison the sensitivity of currently used selection criteria are in the range of 25% to 30%. CONCLUSION: The inclusion of morphologic and immunohistochemical features of breast cancers in algorithms to predict the likelihood of presence of germline mutations in the BRCA1 gene improves the accuracy of the selection process.

Adult↗
PubMed2001

Parental communication of BRCA1/2 genetic test results to children.

The aim of this study was to evaluate the likelihood, correlates, and psychological impact of parental communication to children of parents' BRCA1/2 genetic test results for breast cancer risk. Subjects were 133 adult members of high risk families. Sociodemographic, clinical, and psychological distress variables were assessed during a baseline telephone interview conducted prior to patient education and test result notification. Parental communication of test results to children and parental psychological distress and coping efforts were assessed 1 month post-genetic counseling and receipt of test results. Mothers (versus fathers), and persons with higher levels of baseline general distress, were significantly more likely to communicate their test results to children. Post-counseling coping efforts, both active and avoidant, were positively associated with post-counseling distress levels. However, communication of test results to children did not relate to changes in distress. In conclusion, parents with higher levels of pre-counseling general psychological distress may be more likely to communicate their genetic test results to children; however, this act does not minimize their distress and could possibly generate distress in their youngsters. Research is needed to evaluate the process and content of post-test disclosure episodes and the impact on participant, child, and family functioning.

Adaptation, Psychological↗
PubMed2005

Predictive genetic testing for Alzheimer's disease: impact upon risk perception.

UNLABELLED: The aim of this study was to determine the impact on risk perceptions of disclosing genetic test results used to estimate the risk of Alzheimer's disease (AD). Adult children (n = 149) of people with AD were randomized to one of two groups--Intervention group: lifetime risk estimates of AD based on age, gender, family history, and Apolipoprotein E (APOE) genotype; CONTROL GROUP: lifetime risk estimates of AD based on the same risk factors excluding APOE genotype. Perceptions of personal risk (PPR) for AD were assessed six weeks after risk assessments. PPR were correlated with actual lifetime risk estimates (r = 0.501; p < 0.0001). After controlling for lifetime risks communicated to participants, age, and number of affected relatives, PPR scores among those with an epsilon4-positive test result (the test result associated with increased AD susceptibility) (adjusted mean: 3.4 (SD: 0.7)) were not different from the PPR scores in the CONTROL GROUP (adjusted mean: 3.4 (SD: 0.7) (F1,91= 1.98; p = 0.162). Again, controlling for lifetime risk estimates, age, and number of affected relatives, the PPR score of those receiving an epsilon4-negative test result was significantly lower (adjusted mean: 3.1 (SD: 0.8)) than those in the CONTROL GROUP (adjusted mean: 3.4 (SD: 0.7) (F1,95 = 6.23; p = 0.014). Perceptions of risk of developing AD are influenced by genetic test disclosure in those receiving epsilon4-negative, but not those receiving epsilon4-positive test results. Despite the reduced perceptions of risk in the former group, there was no evidence of false reassurance (i.e., perceiving risks as equal to or lower than population risks of AD), although this possibility should be assessed in other testing contexts.

Age Factors↗