Predictive Genetic Testing Research Articles

Psychological Impact of Predictive Genetic Testing in VCP Inclusion Body Myopathy, Paget Disease of Bone and Frontotemporal Dementia.

Inclusion Body Myopathy associated with Paget's disease of bone and Fronto-temporal Dementia, also known as multisystem proteinopathy is an autosomal dominant, late onset neurodegenerative disorder caused by mutations in Valosin containing protein (VCP) gene. This study aimed to assess uptake and decision making for predictive genetic testing and the impact on psychological well-being. Individuals who had participated in the gene discovery study with a 50 % a priori risk of inheriting VCP disease were sent a letter of invitation offering genetic counseling and testing and were also invited to participate in this psychosocial study. A total of 102 individuals received an invitation and 33 individuals participated in genetic counseling and testing (32.3 %) with 29 completing baseline questionnaires. Twenty completed the follow-up post-test Hospital Anxiety and Depression Scale questionnaire including 13 of the 18 who had tested positive. Mean risk perception at baseline was 50.1 %. Reasons for testing included planning for the future, relieving uncertainty, informing children and satisfying curiosity. At baseline, one quarter of the participants had high levels of anxiety. However, scores were normal one year following testing. In this small cohort, one third of individuals at 50 % risk chose pre-symptomatic testing. Although one quarter of those choosing testing had high anxiety at baseline, this was not evident at follow-up.

Ethical issues in genetics and public health in Latin America with a focus on Argentina.

This paper reviews the health situation and developments in medical genetics and bioethics in Latin America, with a focus on Argentina. The region is the most inequitable in the world, with an average Gini Index of 52.5 and 25% of the population living in poverty. Health expenditures are low and health systems are fragmented and privatised, with curtailed governmental responsibility and regulation. Health-care decision making is mostly in the hands of private insurance corporations and the medical-industrial complex, so that what is (or is not) covered by health plans is arbitrary and determined by the market and not by population health needs. This inequity and the lack of meaningful governmental intervention in the provision of health care, including genetic services, are at the heart of the bioethical dilemmas in Latin America. It is not surprising, therefore, that bioethics in the region has developed an approach grounded in social justice, equity and human rights as guiding principles, in contrast to the individualism espoused by Anglo-Saxon bioethics. The main ethical issues identified in genetics in Latin America are (1) inequity in access to genetic services, particularly in prenatal diagnosis, (2) genetic discrimination and (3) the lack of adherence to internationally accepted requisites of clinical validity and utility for diagnostic and predictive genetic testing. In this context, there is a risk that the impressive advances in genetics/genomics occurring in developed countries may fail to improve the public's health and deepen inequity, with the implementation of expensive genetic technologies of unproven validity.

Do Attachment Style and Emotion Regulation Strategies Indicate Distress in Predictive Testing?

Predictive genetic testing for a neurogenetic disorder evokes strong emotions, and may lead to distress. The aim of this study is to investigate whether attachment style and emotion regulation strategies are associated with distress in persons who present for predictive testing for a neurogenetic disorder, and whether these psychological traits predict distress after receiving test results. Self-report scales were used to assess attachment insecurity (anxiety and avoidance) and maladaptive emotion regulation strategies (self-blame, rumination, catastrophizing) in adults at 50 % risk for Huntington’s Disease (HD), Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), and Hereditary Cerebral Hemorrhage With Amyloidosis - Dutch type (HCHWA-D), when they presented for predictive testing. Distress was measured before testing and twice (within 2 months and between 6 and 8 months) after receiving test results. Pearson correlations and linear regression were used to analyze whether attachment style and emotion regulation strategies indicated distress. In 98 persons at risk for HD, CADASIL, or HCHWA-D, attachment anxiety and catastrophizing were associated with distress before predictive testing. Attachment anxiety predicted distress up to 2 months after testing. Clinicians may consider looking for signs of attachment anxiety and catastrophizing in persons who present for predictive testing, to see who may be vulnerable for distress during and after testing.

Predictive genetic testing in minors for Myocilin juvenile onset open angle glaucoma.

Myocilin glaucoma is an autosomal dominant disorder leading to irreversible blindness, but early intervention can minimize vision loss and delay disease progression. The purpose of this study was to discuss the benefits of predictive genetic testing in minors for Myocilin mutations associated with childhood onset glaucoma. Three families with Myocilin mutations associated with an age of onset before 18 years and six unaffected at-risk children were identified. Predictive genetic testing was discussed with the parents and offered for at-risk minors. Parents opted for genetic testing in half of the cases. None carried the familial mutation. The age of disease onset in the family, the severity of the condition, and the age of the child are all factors that appear to influence the decision of the parent to test their children. Predictive genetic testing for early onset Myocilin glaucoma can facilitate early detection of disease or discharge from routine ophthalmic examinations.

Maximising the efficiency of clinical screening programmes: balancing predictive genetic testing with a right not to know.

We explored the dilemma between patients' right not to know their genetic status and the efficient use of health-care resources in the form of clinical cancer screening programmes. Currently, in the Netherlands, 50% risk carriers of heritable cancer syndromes who choose not to know their genetic status have access to the same screening programmes as proven mutation carriers. This implies an inefficient use of health-care resources, because half of this group will not carry the familial mutation. At the moment, only a small number of patients are involved; however, the expanding possibilities for genetic risk profiling means this issue must be addressed because of potentially adverse societal and financial impact. The trade-off between patients' right not to know their genetic status and efficient use of health-care resources was discussed in six focus groups with health-care professionals and patients from three Dutch university hospitals. Professionals prefer patients to undergo a predictive DNA test as a prerequisite for entering cancer screening programmes. Professionals prioritise treating sick patients or proven mutation carriers over screening untested individuals. Participation in cancer screening programmes without prior DNA testing is, however, supported by most professionals, as testing is usually delayed and relatively few patients are involved at present. Reducing the number of 50% risk carriers undergoing screening is expected to be achieved by: offering more psychosocial support, explaining the iatrogenic risks of cancer screening, increasing out-of-pocket costs, and offering a less stringent screening programme for 50% risk carriers.

0488: Predictive genetic testing in hereditary heart diseases: a single-center series of 304 subjects

Hereditary heart diseases are typically characterized by autosomal dominant inheritance and delayed cardiac expression. Predictive genetic testing is offered to asymptomatic relatives to allow targeted medical care with early therapeutics in order to reduce the risk of complications (sudden death, heart failure). Psychological and sociological issues related to predictive testing are however complex and have been poorly studied. Predictive genetic testing is performed in our multidisciplinary out-patient clinic dedicated to cardiogenetics since 1999. To evaluate our practices regarding predictive genetic testing for hereditary heart diseases and study the behavior of relatives after pre-test consultation (information phase), especially regarding a waiting period that was offered before blood sampling. We retrospectively studied records from 304 consecutive relatives seen in our department and have requested predictive genetic testing. Underlying diseases in the families were HCM (60%), DCM (17%), ARVC (15%), LQT (5%), Brugada syndrome (2%) and other (1%). A total of 21 different genes were analyzed and most frequent ones were MYBPC3 (97), MYH7 (77), LMNA (37), PKP2 (29) and TNNT2 (16). There were 260 adults and 44 minors. At the time of the first consultation, the average age was 37 years, and 83% of the relatives previously had a cardiac checkup (echocardiography for 71%). After first multidisciplinary consultation, 22 relatives (8%) dropped out of procedure (did not performed blood sampling) and 11 relatives (3%) performed blood sampling but did not come back to know their results. Blood sample was delayed for 70% of relatives and immediate for 30%. A mutation was present in 36% of relatives (leading to careful follow-up and cascade screening in offspring) and absent in 64% (they were reassured and discharged from clinic). We observed a high level of genetic uptake after initial consultation but a minority of relatives decided to stop or delay the procedure. These results suggest the benefit of a waiting period before blood sampling and illustrate the importance of a multidisciplinary team in this setting.

0486: Postmortem genetic testing in a series of 36 young patients after sudden cardiac death

The incidence of sudden cardiac death (SCD) increases with age in parallel with coronary’s diseases’ prevalence. In young persons and athletes, SCD occurs in half of the cases, in the setting of genetically transmitted disorders such as cardiomyopathies. Molecular testing performed after necropsy may help management of families but experience in this area appears very limited. The aim is to report our experience of post mortem molecular testing after SCD and necropsy. We studied 36 patients <40 years who died suddenly with a suspected diagnosis of cardiomyopathy, established either after autopsy or known before death, with 6 dilated cardiomyopathy (DCM), 12 hypertrophic (HCM), 2 HCM/DCM, 1 restrictive (CMR), 14 arrhythmogenic right ventricular cardiomyopathy (ARVC), 1 HMC and left ventricular noncompaction. Sanger sequencing was performed in most 4-5 frequent genes for a given phenotype. Fifteen mutations have been identified in sarcomeric (11 mutations) or desmosomal (3 mutations) or lamin (1 mutation) genes. The identification of these mutations had significant impact: assessing right diagnosis in a doubtful case (HCM without LVH), modifying the appropriate diagnosis in another case (HCM and not DCM), confirming a genetic disease even in the absence of affected relatives in the family, providing guidance for genetic counselling and predictive genetic testing in relatives in all situations. Technical, ethical and legal issues may however be encountered and will be discussed. This study is one of rare series of post-mortem molecular testing after SCD. Our findings suggest the feasibility, molecular efficiency and the clinical benefit of the approach in order to improve the management of families. Postmortem molecular testing must take its place in the strategy of family care after SCD, even if a cardiomyopathy is suspected at necropsy, since genetic findings provide additional information useful for the relatives.

Maturity-Onset Diabetes of the Young: What Do Clinicians Need to Know?

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes that is characterized by an early onset, autosomal dominant mode of inheritance and a primary defect in pancreatic β-cell function. MODY represents less than 2% of all diabetes cases and is commonly misdiagnosed as type 1 or type 2 diabetes mellitus. At least 13 MODY subtypes with distinct genetic etiologies have been identified to date. A correct genetic diagnosis is important as it often leads to personalized treatment for those with diabetes and enables predictive genetic testing for their asymptomatic relatives. Next-generation sequencing may provide an efficient method for screening mutations in this form of diabetes as well as identifying new MODY genes. In this review, I discuss a current update on MODY in the literatures and cover the studies that have been performed in Korea.

Should life insurers have access to genetic test results?

Should life insurers have access to genetic test results?

Ethical issues in predictive testing for Huntington's disease an evidence based case discussion

Purpose – Diagnosis of Huntington's disease (HD) is with genetic tests and predictive testing for HD has been available for almost two decades. In the age of advancing genetic techniques, the question arises as to how the predictive tests can affect a person, his or her family and relatives, life choices and future. The paper aims to discuss these issues. Design/methodology/approach – A case study is presented demonstrating the complex issues surrounding genetic testing in HD. Relevant literature was then reviewed to further explore ethical issues linked to predictive testing for HD and also looked into findings on resolving this complex issue. Findings – Predictive testing in HD gives rise to ethical issues in social, legal, economical and imperatively personal aspects of an individual and society. Education and dispersion of knowledge to general society, regarding the test, its impact and also the illness would be a starting point in an attempt to resolve these issues. Need for counselling and support for patients in this context is vital and hence the imperative need to ensure provisions for standardised training and supply of professionals in this setting. Universal and enforceable framework along the lines of International Huntington Association recommendation should be adopted nationally. Originality/value – This paper presents a case study with significant value in demonstrating the challenges faced by genetic testing in HD, and provides insight in to this issue significant for all clinicians.

Predictive genetic testing for adult-onset disorders in minors: a critical analysis of the arguments for and against the 2013 ACMG guidelines.

The publication of the ACMG recommendations has reignited the debate over predictive testing for adult-onset disorders in minors. Response has been polarized. With this in mind, we review and critically analyze this debate. First, we identify long-standing inconsistencies between consensus guidelines and clinical practice regarding risk assessment for adult-onset genetic disorders in children using family history and molecular analysis. Second, we discuss the disparate assumptions regarding the nature of whole genome and exome sequencing underlying arguments of both supporters and critics, and the role these assumptions play in the arguments for and against reporting. Third, we suggest that implicit differences regarding the definition of best interests of the child underlie disparate conclusions as to the best interests of children in this context. We conclude by calling for clarity and consensus concerning the central foci of this debate.

The psychological impact of predictive genetic testing for Huntington's disease: a systematic review of the literature.

Huntington's disease (HD) is a neurodegenerative genetic condition for which a predictive genetic test by mutation analysis has been available since 1993. However, whilst revealing the future presence of the disease, testing may have an adverse psychological impact given that the disease is progressive, incurable and ultimately fatal. This review seeks to systematically explore the psychological impact of genetic testing for individuals undergoing pre-symptomatic mutation analysis. Three databases (Medline, PsycInfo and Scopus) were interrogated for studies utilising standardised measures to assess psychological impact following predictive genetic testing for HD. From 100 papers initially identified, eight articles were eligible for inclusion. Psychological impact of predictive genetic testing was not found to be associated with test result. No detrimental effect of predictive genetic testing on non-carriers was found, although the process was not found to be psychologically neutral. Fluctuation in levels of distress was found over time for carriers and non-carriers alike. Methodological weaknesses of published literature were identified, notably the needs of individuals not requesting genetic testing, as well as inadequate support for individuals registering elevated distress and declining post-test follow-up. Further assessment of these vulnerable individuals is warranted to establish the extent and type of future psychological support.

Reproductive decision-making among individuals at risk for familial amyotrophic lateral sclerosis

This qualitative study explored the reproductive decision-making process in individuals at 50% risk for familial amyotrophic lateral sclerosis (FALS) from families with a known genetic mutation. We spoke with 10 individuals utilizing a semi-structured interview. Participants had a first-degree relative with FALS, made reproductive decisions in the past 30 years and did not know their genetic status during decision-making. We delineated themes emerging in individuals who chose to have children, those who chose not to have children, and themes describing the process in general. Results showed that those who chose to have children believed that regardless of disease, life is productive. They compared ALS relatively favorably to other diseases, always planned on having children, and hoped for a cure. Individuals who chose not to have children had extensive experience with ALS and caretaking, saw ALS as an inevitable tragedy, and avoided serious relationships. In consultation with partners, individuals considered other reproductive options. Conversations varied in length, and often strengthened relationships. Children experiencing death of a parent was a primary concern. In conclusion, the reproductive decision-making process is complex. Results can guide future research and provide direction for healthcare professionals when discussing the family planning process and prior to predictive genetic testing.

A11 Reviewing Progress To Date In HD

<h3></h3> Huntington disease (HD) is a progressive autosomal dominant disorder, for which no disease modifying treatments are currently available. There is however, the potential to develop early therapeutic interventions that will prevent or delay disease onset; as predictive genetic testing can identify individuals who have inherited the gene mutation prior to the onset of HD symptoms. Robust biomarkers for premanifest and early HD are needed to facilitate upcoming clinical trials. Current efforts to develop biomarkers for premanifest and early HD will be reviewed, and potential clinical, cognitive, neuroimaging and biochemical biomarkers will be discussed in terms of their potential for use in HD clinical trials and utility in the development of future treatments for HD.

E25 Fmri Signal Changes In Frontal Cortex Correlates With Years-to-disease-onset In A Group Of Young Premanifest Huntington Disease Subjects

Objective A functional MRI (fMRI) study to identify and localise the earliest neural changes, in a group of young premanifest Huntington’s disease (preHD) individuals, far from estimated clinical onset. Methods Sixteen preHD, and 18 age/sex matched healthy participants were enrolled. All preHD subjects previously underwent the predictive genetic testing for HD, and did not present neurological signs consistent with HD clinical onset (UHDRS TMS score = 0). Cognitive evaluation of both groups of subjects did not reveal abnormalities. The subjects were submitted to volumetric MRI and fMRI, during the execution of the exogenous covert orienting of attention task. Considering the fMRI task (Posner paradigm) correlation analyses were restricted to the frontal oculomotor cortex identified by the means of a prosaccadic task. In preHD group, multiple regression analysis was performed between fMRI results and the probability to develop the disease onset in the next 5 years (p5HD). Results fMRI task behavioural performance did not differ between the two groups, while, mean BOLD signal changes of oculomotor frontal cortex was significantly different in the two groups, and, in preHD, correlates with p5HD (r2 = 0.52). A modest correlation (r2 = 0.29) was observed between right putamen volume and p5HD. Conclusion fMRI activations in the right frontal cortex, correlates with p5HD in a group of preHD individuals very far from onset. This result needs to be confirmed in a larger cohort of preHD subjects enrolled in a longitudinal study, and could represent a possible fMRI biomarker for preHD.

K07 Predictive Genetic Testing For Huntington's Disease At University Hospital Of Uppsala

Background Predictive testing for gene mutation that causes Huntington9s disease allows people who are at risk to find out if they will develop HD later on. People who want predictive testing usually come to a specialist clinic for several counselling appointments. Predictive testing offers a process following international guidelines as the process is a stressful period for both the risk persons and their relatives. The guidelines are designed to make sure that the people thinking about getting tested have enough information and time to make whatever decision is right for them. Aim Give the risk persons up-to-date relevant clinical and genetic information so that they can make an informed, voluntary decision. It is important to discuss and carefully weigh the pros and cons before predictive testing. Ensure the patient follow-up support after the test and regardless of the result. Methods The test procedure includes visits to a doctor for review of the family9s medical history and several visits to a psychologist/ genetic counsellor for processing and mental preparation. We do what we can not to speed up the process, but rather encourage the patients to take their time and also securing them the right to cancel the process if desired. The test result is given by the doctor and psychologist together and the tested person is always offered follow-up, individually or by participation in a conversation and support group. Results and Conclusions Since 2001 we have performed predictive testing of 134 individuals. 66 individuals was found to be carriers, 37 men, 29 women. The conversation and support group started two years ago and has seven members, three men and four women between the age of 28 and 54.

Molecular analysis of the APC gene in Sicilian patients with familial adenomatous polyposis (F.A.P.)

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited syndrome, caused by germline mutations in the adenomatous polyposis coli (APC) suppressor gene. Patients with colorectal polyps are more likely to develop a malignant condition with poor prognosis. Typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by several extra-colonic manifestations; an attenuated form of polyposis (AFAP), presenting less than 100 adenomas and later onset, has been reported.In this study we have examined five Sicilian families affected by FAP syndrome, in order to provide predictive genetic testing for the affected families, as well as to contribute to mutation catalog enrichment.We have detected different APC mutations in these five pedigrees, confirming the remarkable heterogeneity of the mutational spectrum in FAP.

Subtle Psychosocial Sequelae of Genetic Test Results

Research using standard psychological measures has not revealed a dramatic psychological reaction to receipt of predictive genetic test results. Qualitative research, however, indicates that there are subtle psychosocial sequelae of receiving such results that should be considered by individuals and their clinicians prior to testing. Among these more subtle, but burdensome sequelae of testing are (i) changed social relationships (including relationships with clinicians), (ii) the impact of test results on important life decisions (e.g., career and reproductive choices), and (iii) altered self-concept among those tested. This review examines these more subtle sequelae, as well as the inadequacy of existing quantitative measures for assessing their impact, and discusses the relevance of such sequelae for decision-making about predictive genetic testing.

Genetic testing in inherited polyposis syndromes – how and why?

There have been recent advances in genetic testing enabling accurate diagnosis of polyposis syndromes by identifying causative gene mutations, which is essential in the management of individuals with polyposis syndrome and predictive genetic testing of their extended families. There are some similarities in clinical presentation of various polyposis syndromes, which may pose a challenge to diagnosis. In this review, we discuss the clinical presentation of the main polyposis syndromes and the process of genetic testing, including the latest advancement and future of genetic testing. We aim to reiterate the importance of genetic testing in the management of polyposis syndromes, potential pitfalls associated with genetic testing and recommendations for healthcare professionals involved with the care of polyposis patients.

Direct-to-Consumer Advertising of Predictive Genetic Tests: A Health Belief Model Based Examination of Consumer Response

Direct-to-consumer (DTC) advertising of predictive genetic tests (PGTs) has added a new dimension to health advertising. This study used an online survey based on the health belief model framework to examine and more fully understand consumers' responses and behavioral intentions in response to a PGT DTC advertisement. Overall, consumers reported moderate intentions to talk with their doctor and seek more information about PGTs after advertisement exposure, though consumers did not seem ready to take the advertised test or engage in active information search. Those who perceived greater threat from the disease, however, had significantly greater behavioral intentions and information search behavior.