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.

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.

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.

Bloom syndrome does not always present with sun-sensitive facial erythema.

Bloom syndrome is an autosomal recessive condition characterized by severe pre- and postnatal growth deficiency, immunodeficiency, an increased risk for malignancies, craniofacial dysmorphisms, and "typical" erythematous sun-sensitive skin lesions of the face. This facial rash has a butterfly-shaped distribution around the nose and is usually observed for the first time during the early years of life. Though reported as being a main feature of Bloom syndrome, there seems to be phenotypic variability regarding this facial skin rash among patients. It has been previously reported that in some individuals with Bloom syndrome these sun-sensitive lesions are less prominent or even absent. In this report we describe a 36 year old woman with short stature, microcephaly, several dysmorphisms, congenital hypothyroidism and premature ovarian failure. She was diagnosed with nasopharyngeal carcinoma at 36 years of age, only a few months after her consultation at the department of Clinical Genetics. Whole Exome Sequencing demonstrated that she had Bloom syndrome caused by a compound heterozygous mutation in BLM (c.2207_2212delinsTAGATTC; p.(Tyr736Leufs*5) and c.3681del; p.(Lys1227Asnfs*52)). She did not have facial sun-sensitive erythematous rash during childhood nor adulthood. We conclude that Bloom syndrome does not always present with erythematous sun-sensitive skin lesions of the face. We would like to underline that phenotypic variation regarding this "hallmark" feature of Bloom syndrome exists. Being aware of this might prevent a delay in diagnosing this rare short-stature syndrome and, subsequently, its potential clinical implications.

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.

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.

Hypomorphic NOTCH3 alleles do not cause CADASIL in humans.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by stereotyped missense mutations in NOTCH3. Whether these mutations lead to the CADASIL phenotype via a neomorphic effect, or rather by a hypomorphic effect, is subject of debate. Here, we report two novel NOTCH3 mutations, both leading to a premature stop codon with predicted loss of NOTCH3 function. The first mutation, c.307C>T, p.Arg103*, was detected in two brothers aged 50 and 55 years, with a brain MRI and skin biopsy incompatible with CADASIL. The other mutation was found in a 40-year-old CADASIL patient compound heterozygous for a pathogenic NOTCH3 mutation (c.2129A>G, p.Tyr710Cys) and an intragenic frameshift deletion. The deletion was inherited from his father, who did not have the skin biopsy abnormalities seen in CADASIL patients. These individuals with rare NOTCH3 mutations indicate that hypomorphic NOTCH3 alleles do not cause CADASIL.

[Preconceptional carrier screening should not be delayed]. / Stel preconceptionele dragerschapsscreening niet uit.

Couples who are both carriers of the same autosomal recessive disorder are usually unaware of this fact until a child is born with a serious disorder. Preconceptional carrier screening can make them aware of this risk before pregnancy, and thus allow for informed reproductive decision-making. The Health Council of the Netherlands advised the Dutch government that a programme for preconceptional consultation should be implemented, alongside a large pilot project for preconceptional screening for cystic fibrosis and the haemoglobinopathies, but neither of these has been implemented to date. Future parents now depend on local initiatives, as well as on commercial tests offered via the Internet that may not always pay adequate attention to screening criteria and facilities for counselling. The government should accept responsibility for making clinically beneficial screening methods available within the public healthcare sector.

Legius syndrome in fourteen families.

Legius syndrome presents as an autosomal dominant condition characterized by café-au-lait macules with or without freckling and sometimes a Noonan-like appearance and/or learning difficulties. It is caused by germline loss-of-function SPRED1 mutations and is a member of the RAS-MAPK pathway syndromes. Most mutations result in a truncated protein and only a few inactivating missense mutations have been reported. Since only a limited number of patients has been reported up until now, the full clinical and mutational spectrum is still unknown. We report mutation data and clinical details in fourteen new families with Legius syndrome. Six novel germline mutations are described. The Trp31Cys mutation is a new pathogenic SPRED1 missense mutation. Clinical details in the 14 families confirmed the absence of neurofibromas, and Lisch nodules, and the absence of a high prevalence of central nervous system tumors. We report white matter T2 hyperintensities on brain MRI scans in 2 patients and a potential association between postaxial polydactyly and Legius syndrome.

Preconceptional ancestry-based carrier couple screening for cystic fibrosis and haemoglobinopathies: what determines the intention to participate or not and actual participation?

This paper explores determinants of the intention to participate or not and of actual participation in preconceptional ancestry-based carrier couple screening for cystic fibrosis (CF) and haemoglobinopathies (HbPs). In total, 9453 individuals from a multi-ethnic population were invited. Invitees who had a partner and who were planning a pregnancy were the target population (33-36%). Test participation was conditional on survey participation. Those who refrained from test participation were asked to participate in the survey only. The questionnaire was based on the Theory of Planned Behaviour, which explains behaviour through intention. It was completed by 418 survey participants: 171 who intended to participate in the testing, and 247 who refrained from test participation. Both test intenders and offer decliners generally had a positive attitude towards test participation, and perceived high behavioural control. This applied to Western and non-Western survey participants equally. Offer decliners, however, perceived less control in terms of the time and effort needed for participation. Still, 68% of them intended to participate in the future if the screening would be offered routinely. Test intenders more often would draw reproductive consequences from test results, perceived a higher risk of being a carrier, more benefits and less adverse psychological outcomes. Feelings of stigmatisation were not an important issue, but 14% thought that there would be discrimination against carriers: among them more were non-Western survey participants. Preconceptional ancestry-based CF and HbPs carrier screening was evaluated as positive and desirable among Western and non-Western survey participants. The effort and time needed for participation were important reasons for declining participation, which might be overcome by improving access to the screening.

Three-month follow-up of Western and non-Western participants in a study on preconceptional ancestry-based carrier couple screening for cystic fibrosis and hemoglobinopathies in the Netherlands.

OBJECTIVE: To study psychological outcomes, knowledge, recall and understanding of test-results, satisfaction, and reproductive intentions among 97 Western and 46 non-Western participants in a unique preconceptional carrier screening study for both cystic fibrosis and hemoglobinopathies in a multiethnic population the Netherlands, in which a couple's eligibility for cystic fibrosis and/or hemoglobinopathies testing was based on both partners' ancestry. METHODS: Questionnaires before and after pretest consultation, and 1 week and 3 months after receiving test-results. Three cystic fibrosis and seven hemoglobinopathy carriers were identified, but no carrier couples. RESULTS: Overall, anxiety levels were low, knowledge improved after pretest consultation but decreased after 3 months. Ninety-four percent remembered their test-results. Western compared with non-Western participants had higher knowledge-scores and better understanding of test-results. None of the carriers felt less healthy, six felt relieved, and one felt disappointed. Four carriers were unaware of the residual risk of having an affected child. Participants intended to draw reproductive decisions from test-results, were satisfied, did not regret participation, and did not report major feelings of discrimination or stigmatization. CONCLUSIONS: Similar to previous studies, no major adverse psychological effects were demonstrated among the Western and non-Western participants in this study, and they would draw reproductive decisions on test-results. No arguments for rejecting a combined offer of preconceptional ancestry-based cystic fibrosis and hemoglobinopathies carrier screening were found. An extensive implementation study should be carried out, in which understanding of test-results needs further attention, to investigate whether or not this type of screening should be implemented on a large scale in the Netherlands.

CFTR mutations in Turkish and North African cystic fibrosis patients in Europe: implications for screening.

AIMS: To obtain more insight into the variability of the CFTR mutations found in immigrant cystic fibrosis (CF) patients who are living in Europe now, and to estimate the test sensitivity of different frequently used methods of DNA analysis to detect CF carriers or patients among these Turkish or North African immigrants. METHODS: A survey among 373 European CF centers asking which CFTR mutations had been found in Turkish and North African CF patients. RESULTS: 31 and 26 different mutations were reported in Turkish and North African patients, identifying 64.2% (113/176) and 87.4% (118/135) alleles, respectively (p < 0.001). The mean sensitivity (detection rate) of three most common CFTR mutation panels to detect these mutations differed between Turkish and North African people, 44.9% (79/176) versus 69.6% (94/135) (p < 0.001), and can be increased to 57.4% (101/176) and 79.3% (107/135) (p < 0.001), respectively, by expanding these panels with 13 mutations which have been found on two or more alleles. CONCLUSION: 35.8% and 12.6%, respectively, of CF alleles in Turkish and North African patients living in Europe now had not been identified. Among these populations, the test sensitivity of common CFTR mutation panels is insufficient for use in screening programs in Europe, even after expansion with frequent Turkish and North African mutations. This raises questions about whether and how to implement CF carrier and neonatal screening in a multiethnic society.

Implementation of preconceptional carrier screening for cystic fibrosis and haemoglobinopathies: a sociotechnical analysis.

OBJECTIVE: To obtain more insight into the process of potential implementation of a screening program, which aims to identify carriers of cystic fibrosis and haemoglobinopathies before pregnancy, in order to enable couples at high risk of having a child with these disorders, to make informed reproductive decisions. METHODS: Use of sociotechnical analysis, based on a model of co-evolution between technology and society, and, for comparison, the study of the implementation processes of two already existing health care programs with similar aspects to the screening program at issue. RESULTS: Factors important for success appeared to be the existence of sociotechnical niches, in which technological options can be developed and studied in an experimental setting; a structural approach of providing information to future parents; a party that can articulate demand; governmental involvement in the attunement between various stakeholders; and a screening infrastructure in which large-scale DNA diagnostic services are available. CONCLUSIONS: Successful implementation of preconceptional carrier screening for cystic fibrosis and haemoglobinopathies will depend on changes at both regime and landscape level, including the establishment of a new preconceptional health care setting and a clearly visible public health authority which can coordinate, monitor and evaluate such an initiative in public health care.

Developing and optimizing a decisional instrument using self-reported ancestry for carrier screening in a multi-ethnic society.

PURPOSE: To develop a decisional instrument for ancestry-based cystic fibrosis and/or hemoglobinopathies carrier couple screening in The Netherlands. METHODS: A flowchart (Instrument A) and a questionnaire with maps of geographical areas with originally high cystic fibrosis and hemoglobinopathies carrier frequencies (Instrument B), were developed to support participants in self-assessing their eligibility as a couple for carrier screening for cystic fibrosis and/or hemoglobinopathies. The outcome was compared to the self-reported origin of both partners' ancestors during an in-depth interview. Furthermore, preference for Instrument A or B was determined. RESULTS: Of the 112 participants, 88% (99/112, 95% CI 82-94%) (Instrument A) and 91% (102/112, 95% CI 86-96%) (Instrument B), respectively, arrived at a decision in accordance with their ancestral origin, and 57% (64/112, 95% CI 48-66%) preferred Instrument B. A false negative proportion of 5.5% suggests that some carriers will exclude themselves from screening. Results might improve with minor changes in the instruments with regard to geographic specification, and availability of translated versions. CONCLUSION: A decisional instrument to assess ancestry-based eligibility for cystic fibrosis and/or hemoglobinopathies carrier screening, is now available and can with slight adaptations be used in other countries. The instrument also takes into account the possibility of mixed ancestry.