Predictive Genetic Testing Research Articles

APC transcription studies and molecular diagnosis of familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is characterised by the development of hundreds to thousands of colorectal adenomas and results from inherited or somatic mosaic variants in the APC gene. Index patients with suspected FAP are usually investigated by APC coding region sequence and dosage analysis in a clinical diagnostic setting. The identification of an APC variant which is predicted to alter protein function enables predictive genetic testing to guide the management of family members. This report describes a 4-generation family with a phenotype consistent with FAP, but in which an APC variant had not been identified, despite testing. To explore this further, quantitative PCR (qPCR) was employed to assess APC transcription, demonstrating reduced levels of APC RNA. Next generation sequencing (NGS) identified the APC 5'UTR/ Exon 1 variant, c.-190 G>A, that had been reported previously in an another FAP family with APC allelic imbalance. Quantitative RNA studies and DNA sequencing of the APC promoters/ Exon 1 may be useful diagnostically for patients with suspected FAP when coding region variants cannot be identified.

Planning later life with dementia: comparing family caregivers’ perspectives on biomarkers with laypersons’ attitudes towards genetic testing of dementia prediction

Predictive medicine presents opportunities to consider later life under conditions of illness, such as dementia. This paper examines how family caregivers (N = 27) assess the opportunity of prediction and early diagnosis of dementia for oneself based on their particular experience. Furthermore, it compares their attitudes with laypersons’ attitudes (N = 43) towards genetic testing of APOE. By this, we elaborate how much personal experience impacts anticipation and affects, but also moral attitudes towards predictive medicine. Differences in our settings do not allow for direct comparison, so our analysis focuses on multiple similarities in the assessments of predictive (non-genetic vs. genetic) testing. Groups’ reasoning showed also differences influenced mainly by personal experience. Family caregivers addressed more responsibility towards family and had more hopes into medical treatments. To cope with the disease, they expressed expectations to start with medicine and care decisions as early as possible. Laypersons, however, stressed self-determination more and expressed worries about the influence of the pharmaceutical industry by referring to unnecessary medication and, implicitly, the medicalization of aging.

A tailored approach towards informing relatives at risk of inherited cardiac conditions: study protocol for a randomised controlled trial

IntroductionIn current practice, probands are asked to inform relatives about the possibility of predictive DNA testing when a pathogenic variant causing an inherited cardiac condition (ICC) is identified. Previous research...

SAT-100 “A SWORD OF DAMOCLES”: PATIENT AND CAREGIVER BELIEFS, ATTITUDES AND PERSPECTIVES ON GENETIC SCREENING AND TESTING FOR AUTOSOMAL POLYCYSTIC KIDNEY DISEASE - FOCUS GROUP STUDY

Predictive genetic screening and testing is available for accurate and early diagnosis of hereditary autosomal polycystic kidney disease. However, the complex ethical and psychosocial implications can make decision-making challenging and requires an understanding of the patients’ values, goals and priorities. This study aims to describe patient and caregiver beliefs and expectations regarding genetic screening and testing for autosomal polycystic kidney disease (ADPKD). 154 participants (120 patients and 34 caregivers) aged 18 years and over from eight centers in Australia, France and Korea participated in 17 focus groups. Transcripts were analyzed thematically. We identified five themes: avoiding financial disadvantage (insecurity in the inability to obtain life insurance, limited work opportunities, burden of premature investment); futility in uncertainty (tolerating erratic and diverse manifestation of disease, taking preventative actions in vain, daunted by perplexity of results, risk of inheriting PKD being unknown); lacking autonomy and support in decisions (overwhelmed by ambiguous information, medicalizing family planning, appeasing the family); seizing control of wellbeing (gaining confidence in early detection, allowing preparation for the future, reassurance in family resilience); and anticipating impact on quality of life (comforted by lack of symptoms, judging value of life with PKD). For patients with ADPKD, genetic screening or testing provides an opportunity to take ownership of their health through family planning and preventive measures. However, these decisions can be wrought with tensions and uncertainty about prognostic implications, and the psychosocial and financial consequences of testing. Patient-centered genetic counseling and education that addresses patients’ concerns may support informed decision-making about genetic testing and screening in ADPKD.

Cardiac involvement in storage diseases : Role of genetic diagnostics

In clinical practice cardiac involvement in patients with storage disorders is often diagnosed at alate and advanced stage of the disease with pronounced organ damage. As the currently available targeted therapies can only stop the progress of the disease, a timely diagnosis is of particular relevance. Genetic testing has become increasingly more important in cases of suspected cardiac manifestation in storage disorders. Thereby, diagnostic genetic testing can help to confirm the diagnosis and may also be relevant for therapeutic decision making. In relatives of affected patients predictive genetic testing provides the opportunity for anearly therapeutic intervention.

Impact of Predictive Genetic Testing

Impact of Predictive Genetic Testing

How Uncertainty Influences Lay People's Attitudes and Risk Perceptions Concerning Predictive Genetic Testing and Risk Communication.

The interpretation of genetic information in clinical settings raises moral issues about adequate risk communication and individual responsibility about one’s health behavior. However, it is not well-known what role numeric probabilities and/or the conception of disease and genetics play in the lay understanding of predictive genetic diagnostics. This is an important question because lay understanding of genetic risk information might have particular implications for self-responsibility of the patients.Aim: Analysis of lay attitudes and risk perceptions of German lay people on genetic testing with a special focus on how they deal with the numerical information.Methods: We conducted and analyzed seven focus group discussions (FG) with lay people (n = 43).Results: Our participants showed a positive attitude toward predictive genetic testing. We identified four main topics: (1) Anumeric risk instead of statistical information; (2) Treatment options as a factor for risk evaluation; (3) Epistemic and aleatory uncertainty as moral criticism; (4) Ambivalence as a sign of uncertainty.Conclusion: For lay people, risk information, including the statistical numeric part, is perceived as highly normatively charged, often as an emotionally significant threat. It seems necessary to provide lay people with a deeper understanding of risk information and of the limitations of genetic knowledge with respect to one’s own health responsibility.

Risk Assessment for Huntington's Disease for (Future) Offspring Requires Offering Preconceptional CAG Analysis to Both Partners.

Amongst the main reasons people at risk for Huntington's disease (HD) have for undergoing predictive genetic testing are planning a family and prevention of passing on an expanded CAG-repeat to future offspring. After having received an unfavourable test result, a couple may consider prenatal testing in the foetus or preimplantation genetic diagnostic testing (PGD) in embryos. Testing of the foetus or embryos is possible by means of direct testing of the expanded repeat. Optimal reliability in testing the foetus or embryos requires the establishment of the origin of the repeats of both parents in the foetus. For PGD the analysis is combined with or sometimes solely based on identification of the at-risk haplotype in the embryo. This policy implies that in the context of direct testing, the healthy partner's CAG repeat lengths in the HD gene are also tested, but with the expectation that the repeat lengths of the partner are within the normal range, with the proviso that the partner's pedigree is free of clinically confirmed HD. However, recent studies have shown that the expanded repeat has been observed more often in the general population than previously estimated. Moreover, we have unexpectedly observed an expanded repeat in the non-HD partner in four cases which had far-reaching consequences. Hence, we propose that in the context of reproductive genetic counselling, prior to a planned pregnancy, and irrespective of the outcome of the predictive test in the HD-partner, the non-HD partner should also be given the option of being tested on the expanded allele. International recommendations for predictive testing for HD should be adjusted.

Are young women ready for BRCA testing? Comparing attitudes and comprehension of two age groups of healthy Italian women

BackgroundMutations in the BRCA 1/2 genes increase the risk of developing breast and/or ovarian cancer compared with the general population. However, the risk is low at age 30, and for women younger than 25, no preventive or screening options are available. Scientists wonder whether genetic predictive BRCA testing is appropriate at a very young age. Furthermore, although young women have positive attitudes toward testing, their understanding of genetic information seems scarce. ObjectiveTo assess how young (18–24) versus adult (30–45) women at general population- level risk understand information about BRCA testing. Methods302 women read an informative pamphlet and answered an ad-hoc questionnaire assessing usefulness of the information for decision making, intention to undergo predictive testing, and comprehension (perceived, general, and risk comprehension; open-ended questions). ResultsYounger women had a lower comprehension of important BRCA information; it was more difficult for young women to identify the risk figures of cancer, and they showed errors when answering open-ended questions. LimitationsResults are limited by the study’s hypothetical nature. ConclusionsYoung women seem to have particular difficulty understanding BRCA information. Practice implicationsCounsellors should be aware of the difficulties young women have in understanding information about BRCA predictive testing.

Mental diseases and genetic disposition: ethical aspects

The handling of predictive genetic tests especially in the field of mental diseases requires asensitive approach. In particular internet-based direct-to-consumer offers cannot provide an appropriate interpretation of the onset probabilistic data. Instead, adoctor-patient relationship should cater for clarity through hermeneutic and non-technicistic assistance with respect to the necessity of atest as well as with a view to the interpretation of the test results.

Ethical issues of predictive genetic testing for type 2 diabetes mellitus: Attitude of sindhi community

Ethical issues of predictive genetic testing for type 2 diabetes mellitus: Attitude of sindhi community

How to Integrate Personalized Medicine into Prevention? Recommendations from the Personalized Prevention of Chronic Diseases (PRECeDI) Consortium

Medical practitioners are increasingly adopting a personalized medicine (PM) approach involving individually tailored patient care. The Personalized Prevention of Chronic Diseases (PRECeDI) consortium project, funded within the Marie Skłodowska Curie Action (MSCA) Research and Innovation Staff Exchange (RISE) scheme, had fostered collaboration on PM research and training with special emphasis on the prevention of chronic diseases. From 2014 to 2018, the PRECeDI consortium trained 50 staff members on personalized prevention of chronic diseases through training and research. The acquisition of skills from researchers came from dedicated secondments from academic and nonacademic institutions aimed at training on several research topics related to personalized prevention of cancer and cardiovascular and neurodegenerative diseases. In detail, 5 research domains were addressed: (1) identification and validation of biomarkers for the primary prevention of cardiovascular diseases, secondary prevention of Alzheimer disease, and tertiary prevention of head and neck cancer; (2) economic evaluation of genomic applications; (3) ethical-legal and policy issues surrounding PM; (4) sociotechnical analysis of the pros and cons of informing healthy individuals on their genome; and (5) identification of organizational models for the provision of predictive genetic testing. Based on the results of the research carried out by the PRECeDI consortium, in November 2018, a set of recommendations for policy makers, scientists, and industry has been issued, with the main goal to foster the integration of PM approaches in the field of chronic disease prevention.

Content, evaluations and influences in newspaper coverage of predictive genetic testing: A comparative media content analysis from the United Kingdom and Switzerland.

Predictive genetic testing often entails challenging decisions about preventive measures and uncertain health-related risk predictions. Because of its increasing availability, it is important to assess how to debate it publicly. Newspaper content analysis represents a common and reliable way to investigate public discourse retrospectively. We thus quantitatively compare broadsheet newspaper coverage about predictive genetic testing in the United Kingdom and Switzerland during the period of 2011-2016 regarding content, evaluations, stakeholder influence, and trigger events. British coverage was more extensive and positive and included more personal stories. Swiss coverage had more focus on political issues. Angelina Jolie's announcement about her double mastectomy was the most important coverage trigger. Researchers were the most frequently cited stakeholder group, but stakeholders from government and civil society were also represented. Our results thus reflect a movement toward a more active public engagement with predictive genetic testing. The findings help to improve and enrich public engagement regarding predictive genetic testing.

Practice Variation among an International Group of Genetic Counselors on when to Offer Predictive Genetic Testing to Children at Risk of an Inherited Arrhythmia or Cardiomyopathy.

Cascade predictive genetic testing is available for many families as a means to identify individuals at risk of long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), hypertrophic cardiomyopathy (HCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC). The general issue of offering predictive genetic testing to minors has been an area of ethical debate among genetic counselors and other healthcare professionals for many years. An online questionnaire was circulated to four international genetic counseling associations to assess the views of cardiac genetic counselors regarding when to offer predictive genetic testing to children at risk of LQTS, CPVT, HCM, and ARVC. Analysis was both quantitative and qualitative. The study sample comprised 98 respondents. The majority reported that they offer predictive genetic testing before 5years of age to children at risk of LQTS (83%) and CVPT (75%) and before 10years of age to children at risk of HCM (66%) or ARVC (70%). Influencing factors included country of practice, clinical setting, and years of experience. The rationale provided for when to offer predictive genetic testing is encompassed by the ethical principles of beneficence, non-maleficence, autonomy, and informed consent. In conclusion, significant practice variation exists among cardiac genetic counselors regarding predictive genetic testing for children at risk of an inherited cardiomyopathy. These variations call for more research in the area to assist with the development of evidence-based guidelines.

Ethical, Social and Legal Consequences of Genomic Medicine and Predictive Genetic Testing for Diabetes

Ethical, Social and Legal Consequences of Genomic Medicine and Predictive Genetic Testing for Diabetes

244P - BRCA1/BRCA2 predictive genetic testing in an Irish population: A missed opportunity

244P - BRCA1/BRCA2 predictive genetic testing in an Irish population: A missed opportunity

HLA Alleles and CYP2C9*3 as Predictors of Phenytoin Hypersensitivity in East Asians.

To develop a pre-emptive genetic test that comprises multiple predisposing alleles for the prevention of phenytoin-related severe cutaneous adverse reactions (SCARs), three sets of patients with phenytoin-SCAR and drug-tolerant controls from Taiwan, Thailand, and Japan, were enrolled for this study. In addition to cytochrome P450 (CYP)2C9*3, we found that HLA-B*13:01, HLA-B*15:02, and HLA-B*51:01 were significantly associated with phenytoin hypersensitivity with distinct phenotypic specificities. Strikingly, we showed an increase in predictive sensitivity of concurrently testing CYP2C9*3/HLA-B*13:01/HLA-B*15:02/HLA-B*51:01 from 30.5-71.9% for selecting the individuals with the risk of developing phenytoin-SCAR in Taiwanese cohorts, accompanied by a specificity of 77.7% (combined sensitivity, 64.7%; specificity, 71.9% for three Asian populations). Meta-analysis of the four combined risk alleles showed significant associations with phenytoin-SCAR in three Asian populations. In conclusion, combining the assessment of risk alleles of HLA and CYP2C9 potentiated the usefulness of predictive genetic tests to prevent phenytoin hypersensitivity in Asians.

Perspectives of psychiatric investigators and IRB chairs regarding benefits of psychiatric genetics research

There is hope that psychiatric genetics inquiry will provide important insights into the origins and treatment of mental illness given the burden of these conditions. We sought to examine perspectives of psychiatric genetic investigators regarding the potential benefits of genetic research in general and the potential benefits of genetic research for the diagnosis and treatment of mental illnesses specifically. We compared investigator attitudes with those of chairs of Institutional Review Boards (IRBs) entrusted with evaluating the benefits and risks of human research studies. Two groups directly engaged with the conduct and oversight of psychiatric genetic research were examined (psychiatric investigators, n = 203; IRB Chairs, n = 183). Participants rated 15 survey items regarding current and future benefits of general genetic research, possible benefits of psychiatric genetic research, and the importance to society of genetic vs. non-genetic research examining causes and treatments of illnesses. Investigators and IRB Chairs strongly endorsed the future benefits of general genetic research for society and for the health of individuals; compared to IRB Chairs, investigators were more positive about these benefits. Even after adjusting for demographic variables, psychiatric genetic investigators were significantly more optimistic about genetic research compared with IRB Chairs. Both groups were moderately optimistic about the possible benefits of genetic research related to mental illness. Greater optimism was seen regarding new or personalized medications for mental illnesses, as well as genetic predictive testing of mental illnesses. Greater precision and circumspection about the potential benefits of psychiatric genetic research are needed.

Dealing With BRCA1/2 Unclassified Variants in a Cancer Genetics Clinic: Does Cosegregation Analysis Help?

Background: Detection of variants of uncertain significance (VUSs) in BRCA1 and BRCA2 genes poses relevant challenges for counseling and managing patients. VUS carriers should be managed similarly to probands with no BRCA1/2 variants detected, and predictive genetic testing in relatives is discouraged. However, miscomprehension of VUSs is common and can lead to inaccurate risk perception and biased decisions about prophylactic surgery. Therefore, efforts are needed to improve VUS evaluation and communication at an individual level.Aims: We aimed at investigating whether cosegregation analysis, integrated with a careful review of available functional data and in silico predictions, may improve VUSs interpretation and counseling in individual families.Methods: Patients with Breast Cancer (BC) and/or Ovarian Cancer (OC) fulfilling established criteria were offered genetic counseling and BRCA1/2 testing; VUSs identified in index cases were checked in other relatives affected by BC/OC whenever possible. As an alternative, if BC/OC clustered only in one branch of the family, the parental origin of the VUS was investigated. Public prediction tools and databases were used to collect additional information on the variants analyzed.Results: Out of 1045 patients undergoing BRCA1/2 testing in the period October 2011–April 2018, 66 (6.3%) carried class 3 VUSs. Cosegregation analysis was performed for 13 VUSs in 11 kindreds. Seven VUSs (53.8%) did not cosegregate with breast/ovarian cancer in the family, which provided evidence against their role in cancer clustering in those families. Among the 6 cosegregating VUSs, for two (BRCA1 c.5152+2T>G and BRCA2 c.7975A>G) additional evidence exists from databases and in silico tools supporting their pathogenicity, which reinforces the hypothesis they may have had a predisposing effect in respective families. For the remaining four VUSs (31%), cosegregation analysis failed to provide relevant information.Conclusion: Our findings suggest that cosegregation analysis in a clinical context may be helpful to improve test result interpretation in the specific family and, therefore, should be offered whenever possible. Besides, obtaining and sharing cosegregation data helps gathering evidence that may eventually contribute to VUS classification.

When to Offer Predictive Genetic Testing to Children at Risk of an Inherited Arrhythmia or Cardiomyopathy

When to Offer Predictive Genetic Testing to Children at Risk of an Inherited Arrhythmia or Cardiomyopathy