Genetic Screening-Emerging Issues.

In many countries, some form of genetic screening is offered to all or part of the population, either in the form of well-organized screening programs or in a less formalized way. Screening can be offered at different phases of life, such as preconception, prenatal, neonatal and later in life. Screening should only be offered if the advantages outweigh the disadvantages. Technical innovations in testing and treatment are driving changes in the field of prenatal and neonatal screening, where many jurisdictions have organized population-based screening programs. As a result, a greater number and wider range of conditions are being added to the programs, which can benefit couples' reproductive autonomy (preconception and prenatal screening) and improve early diagnosis to prevent irreversible health damage in children (neonatal screening) and in adults (cancer and cascade screening). While many developments in screening are technology-driven, citizens may also express a demand for innovation in screening, as was the case with non-invasive prenatal testing. Relatively new emerging issues for genetic screening, especially if testing is performed using DNA sequencing, relate to organization, data storage and interpretation, benefit-harm ratio and distributive justice, information provision and follow-up, all connected to acceptability in current healthcare systems.

Clinical impact of additional findings detected by genome-wide non-invasive prenatal testing: Follow-up results of the TRIDENT-2 study.

In the TRIDENT-2 study, all pregnant women in the Netherlands are offered genome-wide non-invasive prenatal testing (GW-NIPT) with a choice of receiving either full screening or screening solely for common trisomies. Previous data showed that GW-NIPT can reliably detect common trisomies in the general obstetric population and that this test can also detect other chromosomal abnormalities (additional findings). However, evidence regarding the clinical impact of screening for additional findings is lacking. Therefore, we present follow-up results of the TRIDENT-2 study to determine this clinical impact based on the laboratory and perinatal outcomes of cases with additional findings. Between April 2017 and April 2019, additional findings were detected in 402/110,739 pregnancies (0.36%). For 358 cases, the origin was proven to be either fetal (n = 79; 22.1%), (assumed) confined placental mosaicism (CPM) (n = 189; 52.8%), or maternal (n = 90; 25.1%). For the remaining 44 (10.9%), the origin of the aberration could not be determined. Most fetal chromosomal aberrations were pathogenic and associated with severe clinical phenotypes (61/79; 77.2%). For CPM cases, occurrence of pre-eclampsia (8.5% [16/189] vs 0.5% [754/159,924]; RR 18.5), and birth weight <2.3rd percentile (13.6% [24/177] vs 2.5% [3,892/155,491]; RR 5.5) were significantly increased compared to the general obstetric population. Of the 90 maternal findings, 12 (13.3%) were malignancies and 32 (35.6%) (mosaic) pathogenic copy number variants, mostly associated with mild or no clinical phenotypes. Data from this large cohort study provide crucial information for deciding if and how to implement GW-NIPT in screening programs. Additionally, these data can inform the challenging interpretation, counseling, and follow-up of additional findings.

Dynamics of reproductive genetic technologies: Perspectives of professional stakeholders.

Reproductive and genetic medicine are evolving rapidly, and new technologies are already impacting current practices. This includes technologies that can identify a couples' risk of having a child with a genetic disorder. Responsible implementation of new technologies requires evaluation of safety and ethics. Valuable insights for shaping governance processes are provided by various stakeholders involved, including healthcare professionals. Their willingness to adopt these technologies and guide the necessary systemic changes is required for the successful implementation of these technologies. In this study, twenty-one semi-structured interviews were conducted with professionals from different disciplines in the field of reproductive and genetic healthcare in the Netherlands. Three emerging technologies were discussed: expanded carrier screening (ECS), non-invasive prenatal diagnosis (NIPD) and germline genome editing (GGE). By probing stakeholders' views, we explored how culture, structure and practice in healthcare is being shaped by innovations and changing dynamics in genetic and reproductive medicine. The general consensus was that the implementation of reproductive genetic technologies nationwide is a slow process in Dutch healthcare. A "typical Dutch approach" emerged that is characterized by restrictive legislation, broad support for people living with disabilities, values of an egalitarian society and limited commercialisation. Different scenarios for embedding ECS in future practice were envisioned, while implementation of NIPD in clinical practice was considered obvious. Views on GGE varied among stakeholders. Previous implementation examples in the Netherlands suggest introduction of new technology involves an organized collective learning process, with pilot studies and stepwise implementation. In addition, introducing and scaling up new technologies is complex due to perceived barriers from the legislative framework and the complex relationship between the government and stakeholders in this area. This paper describes how the international trends and advances of technologies are expected to manifest itself in a national setting.

Views of patients and parents of children with genetic disorders on population-based expanded carrier screening.

OBJECTIVE: Faster and cheaper next generation sequencing technologies have enabled expansion of carrier screening for recessive disorders, potentially facilitating population-based implementation regardless of ancestry or family history. Little is known, however, about the attitudes regarding population-based carrier screening among families with genetic disorders. This study assessed views among parents and patients with a recessive disorder and parents of children with Down syndrome (DS) on expanded carrier screening (ECS). METHOD: In total, 85 patients with various recessive disorders, 110 parents of a child with a recessive disorder and 89 parents of a child with DS participated in an online survey in the Netherlands. Severity of recessive disorders was classified as mild/moderate or severe/profound. RESULTS: The majority of the (parents of) patients with a recessive disorder had a positive attitude towards population-based ECS, including screening for their own or their child's disorder. DS parents were significantly less positive towards ECS. Subgroup analyses showed that the severity of the disorder, rather than being a patient or parent, influences the attitudes, beliefs and intention to participate in ECS. CONCLUSION: Our findings have important implications for future implementation initiatives as they demonstrate the different perspectives from people with experiential knowledge with genetic disorders.

Noninvasive Prenatal Test Results Indicative of Maternal Malignancies: A Nationwide Genetic and Clinical Follow-Up Study.

PURPOSE: Noninvasive prenatal testing (NIPT) for fetal aneuploidy screening using cell-free DNA derived from maternal plasma can incidentally raise suspicion for cancer. Diagnostic routing after malignancy suspicious-NIPT faces many challenges. Here, we detail malignancy suspicious-NIPT cases, and describe the clinical characteristics, chromosomal aberrations, and diagnostic routing of the patients with a confirmed malignancy. Clinical lessons can be learned from our experience. METHODS: Patients with NIPT results indicative of a malignancy referred for tumor screening between April 2017 and April 2020 were retrospectively included from a Dutch nationwide NIPT implementation study, TRIDENT-2. NIPT profiles from patients with confirmed malignancies were reviewed, and the pattern of chromosomal aberrations related to tumor type was analyzed. We evaluated the diagnostic contribution of clinical and genetic examinations. RESULTS: Malignancy suspicious-NIPT results were reported in 0.03% after genome-wide NIPT, and malignancies confirmed in 16 patients (16/48, 33.3%). Multiple chromosomal aberrations were seen in 23 of 48 patients with genome-wide NIPT, and a malignancy was confirmed in 16 patients (16/23, 69.6%). After targeted NIPT, 0.005% malignancy suspicious-NIPT results were reported, in 2/3 patients a malignancy was confirmed. Different tumor types and stages were diagnosed, predominantly hematologic malignancies (12/18). NIPT data showed recurrent gains and losses in primary mediastinal B-cell lymphomas and classic Hodgkin lymphomas. Magnetic resonance imaging and computed tomography were most informative in diagnosing the malignancy. CONCLUSION: In 231,896 pregnant women, a low percentage (0.02%) of NIPT results were assessed as indicative of a maternal malignancy. However, when multiple chromosomal aberrations were found, the risk of a confirmed malignancy was considerably high. Referral for extensive oncologic examination is recommended, and may be guided by tumor-specific hallmarks in the NIPT profile.

Preconception risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease.

BACKGROUND: Globally, about 6% of children are born with a serious birth defect of genetic or partially genetic origin. Carrier screening or testing is one way to identify couples at increased risk of having a child with an autosomal recessive condition. The most common autosomal recessive conditions are thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease, with higher carrier rates in high-risk populations of specific ancestral backgrounds. Identifying and counselling couples at genetic risk of the conditions before pregnancy enables them to make fully informed reproductive decisions, with some of these choices not being available if testing is only offered in an antenatal setting. This is an update of a previously published review. OBJECTIVES: To assess the effectiveness of systematic preconception genetic risk assessment to enable autonomous reproductive choice and to improve reproductive outcomes  in women and their partners who are both identified as carriers of thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease in healthcare settings when compared to usual care. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Registers. Date of latest search of the registers: 04 August 2021. In addition, we searched for all relevant trials from 1970 (or the date at which the database was first available if after 1970) to date using electronic databases (MEDLINE, Embase, CINAHL, PsycINFO), clinical trial databases (National Institutes of Health, Clinical Trials Search portal of the World Health Organization, metaRegister of controlled clinical trials), and hand searching of key journals and conference abstract books from 1998 to date (European Journal of Human Genetics, Genetics in Medicine, Journal of Community Genetics). We also searched the reference lists of relevant articles, reviews and guidelines and also contacted subject experts in the field to request any unpublished or other published trials. Date of latest search of all these sources: 25 June 2021.  SELECTION CRITERIA: Any randomised controlled trials (RCTs) or quasi-RCTs (published or unpublished) comparing reproductive outcomes of systematic preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease when compared to usual care. DATA COLLECTION AND ANALYSIS: We identified 37 papers, describing 22 unique trials which were potentially eligible for inclusion in the review. However, after assessment, we found no RCTs of preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease. MAIN RESULTS: No RCTs of preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease are included. A trial identified earlier has published its results and has subsequently been listed as excluded in this review. AUTHORS' CONCLUSIONS: As there are no RCTs of preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis, or Tay-Sachs disease included in either the earlier or current versions of this review, we recommend considering potential non-RCTs studies (for example prospective cohorts or before-and-after studies) for future reviews. While RCTs are desirable to inform evidence-based practice and robust recommendations, the ethical, legal and social implications associated with using this trial design to evaluate the implementation of preconception genetic risk assessment involving carrier testing and reproductive autonomy must also be considered.  In addition, rather than focusing on single gene-by-gene carrier testing for specific autosomal-recessive conditions as the intervention being evaluated, preconception expanded genetic screening should also be included in future searches as this has received much attention in recent years as a more pragmatic strategy. The research evidence for current international policy recommendations is limited to non-randomised studies.

Preconception expanded carrier screening: Impact of information presented by text or video on genetic knowledge and attitudes.

Preconception expanded carrier screening (ECS) aims to identify couples with an increased risk of having a child with an autosomal recessive (AR) disorder before pregnancy, thereby enabling reproductive choices. Genetic knowledge and experiential knowledge both influence the uptake of ECS. As people in the general public often lack such knowledge, it is essential to provide appropriate and understandable information when offering ECS. This study investigated the effect of an educational video, compared to an educational text, on the knowledge and attitudes toward preconception ECS in the general population. Both the text and video consisted of a brief educational summary on AR inheritance and on the type of disorders included in ECS, with the progressive neurodegenerative condition mucopolysaccharidosis type III (MPS III) as an example. Participants in the reproductive age were invited in collaboration with a research agency. Respondents (N = 789) were offered an educational video prior to completing an online questionnaire that examined genetic knowledge, the perceived severity of MPS III, perceived risk, and attitudes toward ECS. Outcomes were compared to reference data collected previously in which respondents had been offered an educational text (N = 781). We first again studied the attitudes toward ECS in a smaller educational text group (N = 266) in order to assess whether attitudes had changed over time due to increased media coverage on ECS, which did not reveal any significant changes. Respondents who were offered the video had a better genetic knowledge, perceived MPS III as more severe, perceived their risks higher and were more likely to participate in ECS compared to those who were offered text. Online video may well be used as supportive tool to the genetic counseling process, creating more knowledge on ECS and severe genetic disorders included in preconception screening panels.

Do Preferred Risk Formats Lead to Better Understanding? A Multicenter Controlled Trial on Communicating Familial Breast Cancer Risks Using Different Risk Formats.

PURPOSE: Counselees' preferences are considered important for the choice of risk communication format and for improving patient-centered care. We here report on counselees' preferences for how risks are presented in familial breast cancer counseling and the impact of this preferred format on their understanding of risk. PATIENTS AND METHODS: As part of a practice-based randomized controlled trial, 326 unaffected women with a family history of breast cancer received their lifetime risk in one of five presentation formats after standard genetic counseling in three Dutch familial cancer clinics: 1) in percentages, 2) in frequencies ("X out of 100"), 3) in frequencies plus graphical format (10×10 human icons), 4) in frequencies and 10-year age-related risk and 5) in frequencies and 10-year age-related risk plus graphical format. Format preferences and risk understanding (accuracy) were assessed at 2-week follow-up by a questionnaire, completed by 279/326 women. RESULTS: The most preferred risk communication formats were numbers combined with verbal descriptions (37%) and numbers only (26%). Of the numerical formats, most (55%) women preferred percentages. The majority (73%) preferred to be informed about both lifetime and 10-year age-related risk. Women who had received a graphical display were more likely to choose a graphical display as their preferred format. There was no significant effect between the intervention groups with regard to risk accuracy. Overall, women given risk estimates in their preferred format had a slightly better understanding of risk. CONCLUSION: The results suggest that the accuracy of breast cancer risk estimation is slightly better for women who had received this information in their preferred format, but the risk format used had no effect on women's risk accuracy. To meet the most frequent preference, counselors should consider providing a time frame of reference (eg, risk in the next 10 years) in a numerical format, in addition to lifetime risk.

International perspectives on the implementation of reproductive carrier screening.

Reproductive carrier screening started in some countries in the 1970s for hemoglobinopathies and Tay-Sachs disease. Cystic fibrosis carrier screening became possible in the late 1980s and with technical advances, screening of an ever increasing number of genes has become possible. The goal of carrier screening is to inform people about their risk of having children with autosomal recessive and X-linked recessive disorders, to allow for informed decision making about reproductive options. The consequence may be a decrease in the birth prevalence of these conditions, which has occurred in several countries for some conditions. Different programs target different groups (high school, premarital, couples before conception, couples attending fertility clinics, and pregnant women) as does the governance structure (public health initiative and user pays). Ancestry-based offers of screening are being replaced by expanded carrier screening panels with multiple genes that is independent of ancestry. This review describes screening in Australia, Cyprus, Israel, Italy, Malaysia, the Netherlands, Saudi Arabia, the United Kingdom, and the United States. It provides an insight into the enormous variability in how reproductive carrier screening is offered across the globe. This largely relates to geographical variation in carrier frequencies of genetic conditions and local health care, financial, cultural, and religious factors.

TRIDENT-2: National Implementation of Genome-wide Non-invasive Prenatal Testing as a First-Tier Screening Test in the Netherlands.

The Netherlands launched a nationwide implementation study on non-invasive prenatal testing (NIPT) as a first-tier test offered to all pregnant women. This started on April 1, 2017 as the TRIDENT-2 study, licensed by the Dutch Ministry of Health. In the first year, NIPT was performed in 73,239 pregnancies (42% of all pregnancies), 7,239 (4%) chose first-trimester combined testing, and 54% did not participate. The number of trisomies 21 (239, 0.33%), 18 (49, 0.07%), and 13 (55, 0.08%) found in this study is comparable to earlier studies, but the Positive Predictive Values (PPV)-96% for trisomy 21, 98% for trisomy 18, and 53% for trisomy 13-were higher than expected. Findings other than trisomy 21, 18, or 13 were reported on request of the pregnant women; 78% of women chose to have these reported. The number of additional findings was 207 (0.36%); these included other trisomies (101, 0.18%, PPV 6%, many of the remaining 94% of cases are likely confined placental mosaics and possibly clinically significant), structural chromosomal aberrations (95, 0.16%, PPV 32%,) and complex abnormal profiles indicative of maternal malignancies (11, 0.02%, PPV 64%). The implementation of genome-wide NIPT is under debate because the benefits of detecting other fetal chromosomal aberrations must be balanced against the risks of discordant positives, parental anxiety, and a potential increase in (invasive) diagnostic procedures. Our first-year data, including clinical data and laboratory follow-up data, will fuel this debate. Furthermore, we describe how NIPT can successfully be embedded into a national screening program with a single chain for prenatal care including counseling, testing, and follow-up.

Direct-to-consumer carrier screening for cystic fibrosis via a hospital website: a 6-year evaluation.

A Dutch university hospital started offering cystic fibrosis (CF) carrier screening directly to consumers (DTC) through their website in 2010. A 6-year process evaluation was conducted to evaluate the offer. Screening was implemented as intended. However, uptake was lower than expected. Forty-four tests have been requested, partly by couples with a positive family history for CF, which was not the intended target group. Users were generally positive about the screening offer, citing accessibility, ease of testing, anonymity, and perceived shortcomings of regular healthcare as reasons for requesting screening. DTC CF carrier screening via a university hospital website is feasible, but is seldom used. Considering technological advances, continuation of this specific offer is questionable.

Experiences of a High-Risk Population with Prenatal Hemoglobinopathy Carrier Screening in a Primary Care Setting: a Qualitative Study.

Carrier screening for hemoglobinopathies (HbPs; sickle cell disease and thalassemia) aims to facilitate autonomous reproductive decision-making. In the absence of a Dutch national HbP carrier screening program, some primary care midwives offer screening on an ad hoc basis. This qualitative descriptive study explores how pregnant women perceive an offer of HbP carrier screening by their midwife. Semi-structured interviews (n = 26) were conducted with pregnant women at risk of being a HbP carrier, and whom were offered screening at their booking appointment in one of two midwifery practices in Amsterdam. The results showed that half of the respondents were familiar with HbPs. Generally, women perceived the offer of HbP carrier screening as positive, and most women (n = 19) accepted screening. Seven declined, of whom two already knew their carrier status. Important reasons to accept screening were to obtain knowledge about their own carrier status and health of their unborn child, and the ease of the procedure. A multistep process of decision-making was observed, as many women did not give follow-up testing (e.g. partner, invasive diagnostics) much consideration while deciding on accepting or declining HbP screening. Women experienced information overload, and preferred receiving the information at a different moment (e.g. before the intake by a leaflet, or preconceptionally). In conclusion, while prenatal HbP carrier screening is perceived as positive, informed decision-making seems to be suboptimal, and both the content and timing of the information provided needs improvement.

Stakeholder perspectives on the implementation of genetic carrier screening in a changing landscape.

BACKGROUND: In most countries, genetic carrier screening is neither offered, nor embedded in mainstream healthcare. Technological developments have triggered a two-fold transition in carrier screening: the expansion from screening one single disorder to many disorders simultaneously, and offering screening universally, regardless of ancestry. This study aims to identify general and population-specific barriers and needs reflected by stakeholders regarding the implementation of carrier screening in a changing landscape. METHODS: Seventeen semi-structured interviews were conducted with Dutch key stakeholders working in the practical and scientific field of carrier screening. The constellation approach was used to categorise barriers and needs into three levels: culture, structure and practice. RESULTS: Barriers on a cultural level include: undecidedness about the desirability of carrier screening, and a lack of priority of screening in mainstream healthcare. On a structural level barriers included: need for organisational structures in healthcare for embedding carrier screening, need for guidelines, financial structures, practical tools for overcoming challenges during counselling, and a need for training and education of both professionals and the public. A lack of demand for screening by the public, and a need for a division of responsibilities were barriers on a practical level. CONCLUSION: The absence of a collective sense of urgency for genetic carrier screening, a lack of organisational structures, and uncertainty or even disagreement about the responsibilities seem to be important barriers in the implementation of carrier screening. Stakeholders therefore suggest that change agents should be formally acknowledged to strategically plan broadening of current initiatives and attune different stakeholders.

Uptake of prenatal diagnostic testing for retinoblastoma compared to other hereditary cancer syndromes in the Netherlands.

Since the 1980s the genetic cause of many hereditary tumor syndromes has been elucidated. As a consequence, carriers of a deleterious mutation in these genes may opt for prenatal diagnoses (PND). We studied the uptake of prenatal diagnosis for five hereditary cancer syndromes in the Netherlands. Uptake for retinoblastoma (Rb) was compared with uptake for Von Hippel-Lindau disease (VHL), Li-Fraumeni syndrome (LFS), familial adenomatous polyposis (FAP), and hereditary breast ovarian cancer (HBOC). A questionnaire was completed by all nine DNA-diagnostic laboratories assessing the number of independent mutation-positive families identified from the start of diagnostic testing until May 2013, and the number of PNDs performed for these syndromes within these families. Of 187 families with a known Rb-gene mutation, 22 had performed PND (11.8%), this was significantly higher than uptake for FAP (1.6%) and HBOC (<0.2%). For VHL (6.5%) and LFS (4.9%) the difference was not statistically significant. PND for Rb started 3 years after introduction of diagnostic DNA testing and remained stable over the years. For the other cancer syndromes PND started 10-15 years after the introduction and uptake for PND showed an increase after 2009. We conclude that uptake of PND for Rb was significantly higher than for FAP and HBOC, but not different from VHL and LFS. Early onset, high penetrance, lack of preventive surgery and perceived burden of disease may explain these differences.

Factors for successful implementation of population-based expanded carrier screening: learning from existing initiatives.

Background: Carrier screening for autosomal recessive disorders aims to facilitate reproductive decision-making by identifying couples with a 1-in-4 risk in every pregnancy of having an affected child. Except for a few countries or regions, carrier screening is not widely offered and is mostly ancestry-based. Technological advances enable carrier screening for multiple diseases simultaneously allowing universal screening regardless of ancestry (population-based expanded carrier screening). It is important to study how this can be successfully implemented. This study therefore aims to identify critical factors involved in successful implementation, from a user perspective, by learning from already implemented initiatives. Methods: Factors associated with successful implementation were identified by: (i) a literature review and (ii) two case studies; studying experiences with carrier screening in two high-risk communities (a Dutch founder population and the Ashkenazi Jewish population), including a survey among community members. Results: Factors identified were familiarity with (specific) genetic diseases and its availability, high perceived benefits of screening (e.g. screening avoids much suffering), acceptance of reproductive options, perceived risk of being a carrier and low perceived social barriers (e.g. stigmatization). In contrast to the Jewish community, the initial demand for screening in the Dutch founder population did not entirely come from the community itself. However, the large social cohesion of the community facilitated the implementation process. Conclusion: To ensure successful implementation of population-based expanded carrier screening, efforts should be made to increase knowledge about genetic diseases, create awareness and address personal benefits of screening in a non-directive way.

Maternal Plasma DNA and RNA Sequencing for Prenatal Testing.

Cell-free DNA (cfDNA) testing has recently become indispensable in diagnostic testing and screening. In the prenatal setting, this type of testing is often called noninvasive prenatal testing (NIPT). With a number of techniques, using either next-generation sequencing or single nucleotide polymorphism-based approaches, fetal cfDNA in maternal plasma can be analyzed to screen for rhesus D genotype, common chromosomal aneuploidies, and increasingly for testing other conditions, including monogenic disorders. With regard to screening for common aneuploidies, challenges arise when implementing NIPT in current prenatal settings. Depending on the method used (targeted or nontargeted), chromosomal anomalies other than trisomy 21, 18, or 13 can be detected, either of fetal or maternal origin, also referred to as unsolicited or incidental findings. For various biological reasons, there is a small chance of having either a false-positive or false-negative NIPT result, or no result, also referred to as a "no-call." Both pre- and posttest counseling for NIPT should include discussing potential discrepancies. Since NIPT remains a screening test, a positive NIPT result should be confirmed by invasive diagnostic testing (either by chorionic villus biopsy or by amniocentesis). As the scope of NIPT is widening, professional guidelines need to discuss the ethics of what to offer and how to offer. In this review, we discuss the current biochemical, clinical, and ethical challenges of cfDNA testing in the prenatal setting and its future perspectives including novel applications that target RNA instead of DNA.

Attitudes of cystic fibrosis patients and parents toward carrier screening and related reproductive issues.

Cystic fibrosis (CF) is a life-limiting autosomal recessive disorder affecting ~1 in 2500-4000 Caucasians. As most CF patients have no family history of the disorder, carrier screening for CF has the potential to prospectively identify couples at risk of conceiving an affected child. At-risk couples may consequently choose to act on the provided information and take steps to avoid the birth of a child with CF. Although carrier screening is widely believed to enhance reproductive autonomy of prospective parents, the practice also raises important ethical questions. A written questionnaire was administered to adult patients and parents of children with CF with the aim to explore participants' attitudes toward CF carrier screening and related reproductive issues. The study population was recruited from a CF patient registry in Belgium and comprised 111 participants (64 parents, 47 patients aged 16 or older). We found that more than 80% of all participants were in favor of preconception carrier screening for CF. However, some were concerned over potential negative consequences of population-wide CF carrier screening. Regarding future reproductive intentions, 43% of the participants indicated a desire to have children. Among these, preimplantation genetic diagnosis was found to be the most preferred reproductive option, closely followed by spontaneous pregnancy and prenatal diagnosis. Although the findings of our study suggest that patients and parents of children with CF support a population-based carrier screening program for CF, they also highlight some issues deserving particular attention when implementing such a program.

Do Health Professionals Need Additional Competencies for Stratified Cancer Prevention Based on Genetic Risk Profiling?

There is growing evidence that inclusion of genetic information about known common susceptibility variants may enable population risk-stratification and personalized prevention for common diseases including cancer. This would require the inclusion of genetic testing as an integral part of individual risk assessment of an asymptomatic individual. Front line health professionals would be expected to interact with and assist asymptomatic individuals through the risk stratification process. In that case, additional knowledge and skills may be needed. Current guidelines and frameworks for genetic competencies of non-specialist health professionals place an emphasis on rare inherited genetic diseases. For common diseases, health professionals do use risk assessment tools but such tools currently do not assess genetic susceptibility of individuals. In this article, we compare the skills and knowledge needed by non-genetic health professionals, if risk-stratified prevention is implemented, with existing competence recommendations from the UK, USA and Europe, in order to assess the gaps in current competences. We found that health professionals would benefit from understanding the contribution of common genetic variations in disease risk, the rationale for a risk-stratified prevention pathway, and the implications of using genomic information in risk-assessment and risk management of asymptomatic individuals for common disease prevention.

Effect of comprehensive oncogenetics training interventions for general practitioners, evaluated at multiple performance levels.

General practitioners (GPs) are increasingly called upon to identify patients at risk for hereditary cancers, and their genetic competencies need to be enhanced. This article gives an overview of a research project on how to build effective educational modules on genetics, assessed by randomized controlled trials (RCTs), reflecting the prioritized educational needs of primary care physicians. It also reports on an ongoing study to investigate long-term increase in genetic consultation skills (1-year follow-up) and interest in and satisfaction with a supportive website on genetics among GPs. Three oncogenetics modules were developed: an online Continuing Professional Development (G-eCPD) module, a live genetic CPD module, and a "GP and genetics" website (huisartsengenetica.nl) providing further genetics information applicable in daily practice. Three assessments to evaluate the effectiveness (1-year follow-up) of the oncogenetic modules were designed: 1.An online questionnaire on self-reported genetic competencies and changes in referral behaviour, 2.Referral rates from GPs to clinical genetics centres and 3.Satisfaction questionnaire and visitor count analytics of supportive genetics website. The setting was Primary care in the Netherlands and three groups of study participants were included in the reported studies:. Assessment 1. 168 GPs responded to an email invitation and were randomly assigned to an intervention or control group, evaluating the G-eCPD module (n = 80) or the live module (n = 88). Assessment 2. Referral rates by GPs were requested from the clinical genetics centres, in the northern and southern parts of the Netherlands (Amsterdam and Maastricht), for the two years before (2010 [n = 2510] and 2011 [n = 2940]) and the year after (2012 [n = 2875]) launch of the oncogenetics CPD modules and the website. Assessment 3. Participants of the website evaluation were all recruited online. When they visited the website during the month of February 2013, a pop-up invitation came up. Of the 1350 unique visitors that month, only 38 completed the online questionnaire. Main outcomes measure showed long-term (self-reported) genetic consultation skills (i.e. increased genetics awareness and referrals to clinical genetics centres) among GPs who participated in the oncogenetic training course, and interest in and satisfaction with the supportive website. 42 GPs (52%) who previously participated in the G-eCPD evaluation study and 50 GPs (57%) who participated in the live training programme responded to the online questionnaire on long-term effects of educational outcome. Previous RCTs showed that the genetics CPD modules achieved sustained improvement of oncogenetic knowledge and consultation skills (3-months follow-up). Participants of these RCTs reported being more aware of genetic problems long term; this was reported by 29 GPs (69%) and 46 GPs (92%) participating in the G-eCPD and live module evaluation studies, respectively (Chisquare test, p<0.005). One year later, 68% of the respondents attending the live training reported that they more frequently referred patients to the clinical genetics centres, compared to 29% of those who attended the online oncogenetics training (Chisquare test, p<0.0005). However, the clinical genetics centres reported no significant change in referral numbers one year after the training. Website visitor numbers increased, as did satisfaction, reflected in a 7.7 and 8.1 (out of 10) global rating of the website (by G-eCPD and live module participants, respectively). The page most often consulted was "family tree drawing". Self-perceived genetic consultation skills increased long-term and GPs were interested in and satisfied with the supportive website. Further studies are necessary to see whether the oncogenetics CPD modules result in more efficient referral. The results presented suggest we have provided a flexible and effective framework to meet the need for effective educational programmes for non-geneticist healthcare providers, enabling improvement of genetic medical care.