TGFBR3 variation is not a common cause of Marfan-like syndrome and Loeys-Dietz-like syndrome

Marfan syndrome (MFS) is caused by mutations in the fibrillin-1 (FBN1) gene, and mutations in FBN1 are known to be responsible for over 90% of all MFS cases. Locus heterogeneity has also been reported and confirmed, with mutations in the receptor genes TGFBR1 and TGFBR2 identified in association with MFS-related phenotypes. It is now known that dysregulation of TGF-ß signaling is involved in MFS pathogenesis. To test the hypothesis that dysregulation of TGFBR3-associated TGF-ß signaling is implicated in MFS or related phenotype pathogenesis, we selected a cohort of 49 patients, fulfilling or nearly fulfilling the diagnostic criteria for MFS. The patients were known not to carry a mutation in the FBN1 gene (including three 5' upstream alternatively spliced exons), the TGFBR1 and TGFBR2 genes. Mutation screening for the TGFBR3 gene in these patients and in controls led to the identification of a total of ten exonic (one novel), four intronic (one novel) and one 3'UTR variant in the TGFBR3 gene. Our data suggest that variations in TGFBR3 gene appear not to be associated with MFS or related phenotype

General Practitioners and Breast Surgeons in France, Germany, Netherlands and the UK show variable breast cancer risk communication profiles

International audienceBackground: No information is available on the attitudes of General Practitioners (GPs) and Breast Surgeons (BSs) to their delivery of genetic, environmental and lifestyle risk factor information about breast cancer. The aim of this study was to describe the Breast Cancer Risk Communication Behaviours (RCBs) reported by GPs and BSs in four European countries and to determine the relationships between their RCBs and their socio-occupational characteristics. Methods: Self-administered questionnaires assessing breast cancer risk communication behaviours using vignettes were mailed to a sample of Breast Surgeons (BS) and General Practitioners (GP) working in France, Germany, the Netherlands, and the UK (N = 7292). Their responses to questions about the risk factors were first ordered and compared by specialty and country after making multivariate adjustments. Rather than defining a standard Risk Presentation Format (RPF) a priori, the various RPFs used by the respondents were analyzed using cluster analysis. Results: Family history and hormonal replacement therapy were the risk factors most frequently mentioned by the 2094 respondents included in this study. Lifestyle BC risk factors such as obesity and alcohol were rarely/occasionally mentioned, but this point differed (p < 0.001) depending on the country and the specialty of the providers involved. Five distinct RPF profiles including the numerical/verbal presentation of absolute/relative risks were identified. The most frequently encountered RPF (34.2%) was characterized by the fact that it included no negative framing of the risks, i.e., the probability of not developing cancer was not mentioned. Age, specialty and country of practice were all found to be significant determinants of the RPF clusters. Conclusions: The increasing trend for GPs and BSs to discuss lifestyle risk factors with their patients suggests that this may be a relevant means of improving breast cancer prevention. Physicians' risk communication skills should be improved during their initial and vocational training

General practitioner management of genetic aspects of a cardiac disease: a scenario-based study to anticipate providers’ practices

It is increasingly recognised that genetics will have to be integrated into all parts of primary health care. Previous research has demonstrated that involvement and confidence in genetics varies amongst primary care providers. We aimed to analyse perceptions of primary care providers regarding responsibility for genetic tasks and factors affecting those perceptions. Postal questionnaire including a hypothetical case management scenario of a cardiac condition with a genetic component was sent to random samples of medically qualified general practitioners in France, Germany, Netherlands, Sweden and UK (n = 1,168). Logistic regression analysis of factors affecting primary care practitioners’ willingness to carry out genetic tasks themselves was conducted; 61% would take a family history themselves but only 38% would explain an inheritance pattern and 16% would order a genetic test. In multivariate analysis, only the country of practice was consistently predictive of willingness to carry out genetic tasks, although male gender predicted willingness to carry out the majority of tasks studied. The stage of career at which education in genetics had been provided was not predictive of willingness to carry out any of the tasks analysed. Country of practice is significantly predictive of attitudes towards genetics in primary care practice and therefore genetic education structure and content in Europe will need to be significantly tailored towards country-specific approaches

Genetic Testing in Emerging Economies (GenTEE)

Drivers, barriers and opportunities for genetic testing services in emerging economies: the GenTEE (Genetic Testing in Emerging Economies) project Background: Due to the epidemiological transition in the emerging economies of China, East Asia, India, Latin America, the Middle East and South Africa, these economies are facing (i) an increasing proportion of morbidity and mortality due to congenital and genetic conditions, (ii) a rising need for genetic services to improve patient outcomes and overall population health. These economies are facing the challenge how: (i) to ensure the successful translation of genetic/genomics laboratory and academic research into quality assured pathways, (ii) to develop a service delivery infrastructure that leads to equitable and affordable access to high quality genetic/genomic testing services. Objectives: (i) to document and compare current practices and the state of genetic service provision in eight emerging economies: Argentina, Brazil, China, Egypt, India, Oman, Philippines and South Africa, (ii) to identify current knowledge gaps and unmet service needs. The GenTEE international project is intended to inform policy decisions for the challenges of delivering equitable high quality genetic services and to promote international collaboration for capacity building. Methods: (i) a standardized survey that is the first of its worldwide that allows comparison of services internationally across a number of key dimensions by using a core set of indicators, selected by the GenTEE consortium for their relevance and comparability, (ii) capacity building demonstration projects. To date, the GenTEE project has completed its survey that maps the current state of genetic services in the participating countries and identifies current drivers, barriers and opportunities for genetic services development. Results: There is no equitable access to genetic services in all countries mainly due to financial barriers (underfunded fragmented public services, out-of-pocket expenses tend to be the norm for genetic testing services), geographical barriers (concentration of services in main cities) and skill gaps, resulting in inequitable services or delayed access. The development of services in the private sector is opportunistic and mostly technology and market driven. There is a marked lack of standard operating procedures and agreed quality assessment processes for new technologies. Discussion: International collaborative networks can provide support for capacity building and help to strengthen the provision of quality genetic/genomic services in emerging economies.JRC.I.1-Chemical Assessment and Testin

PanelDesign: Integrating Epidemiological Information into the Design of Diagnostic NGS Gene Panels

We report upon PanelDesign, a framework to support the design of diagnostic next generation DNA sequencing panels with epidemiological information. Two publicly available resources, namely Genomics England PanelApp and Orphadata, were combined into a single data set to allow genes in a given NGS panel to be ranked according to the frequency of the associated diseases, thereby highlighting potential core genes as defined by the Eurogenetest/ESHG guidelines for diagnostic next generation DNA sequencing. In addition, PanelDesign can be used to evaluate the contribution of different genes to a given disease following ACMG (American College of Medical Genetics) technical standards

EuroGentest: DNA-based testing for heritable disorders in Europe

Objectives: Regarding the recent attention to develop policies regarding the provision of clinical genetic testing services, access to, acceptance, utilisation and regulation of genetic services was investigated in selected European countries as well as one non-European country. Methods: Data were collected on the basis of relevant international reports and sources accessible via the internet, from self-designed, internationally administered surveys and with the help of a panel of experts from European countries participating in several workshops as well as from National European Societies of Human Genetics. Results: A selection of divergent health care systems was reviewed and compared (e.g. Finland, Germany, Portugal, Sweden, UK, France, Italy, Spain, Czech Republic, Lithuania and Serbia/Montenegro). For the evaluation of clinical validity and utility of genetic testing, background information was provided focussing on DNA-based testing for heritable disorders with a strong genetic component (usually due to the action of a single gene). Conclusions: There is great heterogeneity in genetic testing services among the countries surveyed. It is premature to mandate that genetic testing provided by clinical services meets professional standards regarding clinical validity and utility, because there is to date no consensus within the scientific community and among health care providers to what extent clinical validity and utility can and need to be assessed. Points to consider in the process of developing such standards are proposed

What is ideal genetic counselling? A survey of current international guidelines

The objective of this article is to review guidelines that address counselling in the context of genetic testing in order to summarise what aspects of counselling they consider most important, and to examine how they construct the ideal of genetic counselling. Guidelines were collected by examining the websites of different international professional, political, ethical and patient organisations, either previously known or found with the help of the Google search engine, and also using references listed in other studies. The most frequently mentioned topics in the collected 56 guidelines were sought, and this was carried out with the software package Qualitative Solutions and Research for Non-numerical Unstructured Data Indexing Searching and Theorizing. Topics related to genetic counselling that were mentioned in at least 30 of 56 collected documents were considered to be the most important aspects of genetic counselling. The ideal of genetic counselling is expressed in the analysed guidelines as being composed of (1) an appropriately trained professional who understands genetics and its ethical implications well; (2) relevant and objective information; (3) assurance of the counsellee's understanding; (4) psychological support; (5) informed consent; (6) confidentiality of genetic information; (7) considering familial implications; (8) appropriate handling of potential discrimination of testing; and (9) assuring autonomous decision-making by the counsellee. The ideal of genetic counselling is rather consistent in the guidelines, but there are some contradictions between the requirements of objective information-giving and adapting counselling to counsellee's circumstances