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.

Predictive Value of SLCO1B1 c.521T>C Polymorphism on Observed Changes in the Treatment of 1136 Statin-Users.

Pharmacogenomic testing is a method to prevent adverse drug reactions. Pharmacogenomics could be relevant to optimize statin treatment, by identifying patients at high risk for adverse drug reactions. We aim to investigate the clinical validity and utility of pre-emptive pharmacogenomics screening in primary care, with SLCO1B1 c.521T>C as a risk factor for statin-induced adverse drug reactions. The focus was on changes in therapy as a proxy for adverse drug reactions observed in statin-users in a population-based Dutch cohort. In total, 1136 statin users were retrospectively genotyped for the SLCO1B1 c.521T>C polymorphism (rs4149056) and information on their statin dispensing was evaluated as cross-sectional research. Approximately half of the included participants discontinued or switched their statin treatment within three years. In our analyses, we could not confirm an association between the SLCO1B1 c.521T>C genotype and any change in statin therapy or arriving at a stable dose sooner in primary care. To be able to evaluate the predictive values of SLCO1B1 c.521T>C genotype on adverse drug reactions from statins, prospective data collection of actual adverse drug reactions and reasons to change statin treatment should be facilitated.

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.

[CRISPR gene therapy enters the clinic: the future starts now]. / Genetische reparatie met CRISPR in de kliniek.

In 2020, the Nobel Prize in Chemistry was awarded to American molecular biologist Jennifer Doudna and her French colleague Emmanuelle Charpentier for their fundamental research on CRISPR, an ingenious bacterial immune system. Studies into the working mechanism of CRISPR led to many Eureka moments. Through smart biotechnological engineering, CRISPR became suitable for applications in 'DNA surgery': the targeted editing of the genetic code. Here, we discuss emerging medical CRISPR applications for the treatment of human genetic disorders, including in vivo therapy. This Nobel Prize-winning discovery is powerful, adaptable and accurate, and clinical trials are being launched at an amazing pace. However, extensive research is needed on safe clinical use and possible side effects of CRISPR. In addition, the regulations on market authorization and reimbursement are not yet tailored to this very personal and potentially expensive therapy. Whereas challenges remain, CRISPR gene therapy will continue to rapidly mature as a clinical reality.

Mainstreaming informed consent for genomic sequencing: A call for action.

The wider availability of genomic sequencing, notably gene panels, in cancer care allows for personalised medicine or the tailoring of clinical management to the genetic characteristics of tumours. While the primary aim of mainstream genomic sequencing of cancer patients is therapy-focussed, genomic testing may yield three types of results beyond the answer to the clinical question: suspected germline mutations, variants of uncertain significance (VUS), and unsolicited findings pertaining to other conditions. Ideally, patients should be prepared beforehand for the clinical and psychosocial consequences of such findings, for themselves and for their family members, and be given the opportunity to autonomously decide whether or not to receive such unsolicited genomic information. When genomic tests are mainstreamed into cancer care, so should accompanying informed consent practices. This paper outlines what mainstream oncologists may learn from the ethical tradition of informed consent for genomic sequencing, as developed within clinical genetics. It argues that mainstream informed consent practices should focus on preparing patients for three types of unsolicited outcomes, briefly and effectively. Also, it argues that when the chance of unsolicited findings is very low, opt-out options need not be actively offered. The use of a layered approach - integrated in information systems - should render informed consent feasible for non-geneticist clinicians in mainstream settings. (Inter) national guidelines for mainstreaming informed consent for genomic sequencing must be developed.

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

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

[Polygenic risk prediction of common diseases: from epidemiology to clinical application]. / Polygenetische risicopredictie van veelvoorkomende ziekten.

Since the first map of the human genome was published in 2001 our knowledge about our genetic code has increased exponentially. In addition to high-risk genes for monogenic diseases, such as Huntington's disease and cystic fibrosis, for a number of common diseases, such as breast cancer and cardiovascular disease, many genetic variants that each have a slight increased-risk effect, have been identified via genome-wide association studies (GWAS). A polygenic risk score (PRS) can be calculated on the basis of these single-nucleotide polymorphisms (SNPs), by which an increasingly accurate prediction can be made of an individual's risk for diseases. The results of epidemiological studies in which a PRS is used to predict an individual's total genetic risk for particular diseases are promising. In the future, the PRS could be a valuable addition to traditional monogenic tests. It is, however, important that the predictive value of a genetic risk profile increases further and that it becomes more clear how a clinician must interpret this type of genetic profile - in combination with traditional risk factors.

Moving towards a cure in genetics: what is needed to bring somatic gene therapy to the clinic?

Clinical trials using somatic gene editing (e.g., CRISPR-Cas9) have started in Europe and the United States and may provide safe and effective treatment and cure, not only for cancers but also for some monogenic conditions. In a workshop at the 2018 European Human Genetics Conference, the challenges of bringing somatic gene editing therapies to the clinic were discussed. The regulatory process needs to be considered early in the clinical development pathway to produce the data necessary to support the approval by the European Medicines Agency. The roles and responsibilities for geneticists may include counselling to explain the treatment possibilities and safety interpretation.

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.

DPD Testing Before Treatment With Fluoropyrimidines in the Amsterdam UMCs: An Evaluation of Current Pharmacogenetic Practice.

INTRODUCTION: The fluoropyrimidines (FP) (5-Fluorouracil, capecitabine, and tegafur) are commonly used anti-cancer drugs, but lead to moderate to severe toxicity in about 10-40% of patients. DPD testing [either the enzyme activity of dihydropyrimidine dehydrogenase (DPD) or the DPYD genotype] identifies patients at higher risk for toxicity who may be treated more safely with a lower drug dose. The Netherland's National guideline for colon carcinoma was updated in 2017 to recommend DPYD genotyping before treatment with FP. Pretreatment DPYD genotyping identifies approximately 50% of the patients that will develop severe FP toxicity. The aim of the study was to assess the uptake of DPD testing in the Amsterdam University Medical Centers over time and to evaluate stakeholder experiences to indicate barriers and facilitators of implementation in routine clinical care. MATERIALS AND METHODS: We used a mixed-method approach involving electronic patient records of 753 unique patients and pharmacy information systems analyses and fifteen semi-structured interviews with oncologists, pharmacists, and patients. The constellation perspective was used to identify barriers and facilitators at the level of practice, culture and structure. The proportion of FP users who were DPD tested pretreatment showed an increase from 1% (1/86) in Q2-2017 up to 87% (73/84) in Q4-2018. Unlike a landmark paper published in 2015, the National guideline for colorectal carcinoma followed by meetings to achieve local consensus led to this steep increase in the proportion of patients tested. RESULTS: Facilitating factors for stakeholders to implement testing included the existence of clear protocols, (anecdotal) evidence of the utility, being aware that peers are adhering to standard practice and clear and simple procedures for ordering and reporting. Main barriers included the lack of clear divisions of responsibilities, the lack of consensus on a test approach, long turn-around times and non-user-friendly IT-infrastructures. More professional education on the utility and limitations of pharmacogenetic testing was desired by most stakeholders. CONCLUSION: While the evidence for DPD testing was sufficient, only after the update of a National guideline and local consensus meetings the proportion of FP users that were DPD tested pretreatment rose to 87%. The implementation of personalized medicine requires stakeholders involved to attune practice, culture and structure.

[CRISPR/Cas: technique to repair DNA errors: is a clinical breakthrough near?] / CRISPR/Cas: techniek om DNA-fouten te repareren.

CRISPR/Cas gene editing makes it much easier to make targeted changes in the DNA of human cells than other forms of gene therapy. This revolutionary technology offers spectacular opportunities to study gene functions; the clinical consequences of gene variations in patients can be determined much faster. The efficacy and accuracy of CRISPR/Cas is so impressive that a breakthrough to therapeutic applications is approaching fast. CRISPR/Cas is already being used in immunotherapy against cancer, and trials for monogenetic blood disorders, such as beta-thalassemia, have been scheduled. However, broad clinical implementation of CRISPR/Cas is not feasible yet, due to off-target DNA changes that may occur as a by-product. Particularly in case of in-vivo applications there are therapeutic challenges. For gene editing in human embryos, technical shortcomings and open ethical issues need to be addressed. Gene-editing therapy for serious disorders with transplantable cell types, and therefore the option of verification of "CRISPRed" cells, is seen as a possible first application within the regular healthcare system.

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.

Barriers and Facilitating Factors for Implementation of Genetic Services: A Public Health Perspective.

More than 15 years after the publication of the sequence of the human genome, the resulting changes in health care have been modest. At the same time, some promising examples in genetic services become visible, which contribute to the prevention of chronic disease such as cancer. These are discussed to identify barriers and facilitating factors for the implementation of genetic services. Examples from oncogenetics illustrate a high risk of serious disease where prevention is possible, especially in relatives. Some 5% of breast cancers and colorectal cancers are attributable to an inherited predisposition. These cancers occur at a relatively young age. DNA testing of relatives of affected patients may facilitate primary and secondary prevention. Training of non-genetic health care workers and health technology assessment are needed, as is translational research in terms of bringing genomics to health care practice while monitoring and evaluating. Stratified screening programs could include cascade screening and risk assessment based on family history. New roles and responsibilities will emerge. A clear assessment of the values implied is needed allowing to balance the pros and cons of interventions to further the responsible innovation of genetic services.

Aggregated N-of-1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis.

BACKGROUND: Inexpensive medicines with a long history of use may currently be prescribed off-label for rare indications. Reimbursement is at the discretion of health insurance companies, and may be unpredictable. The example addressed was ephedrine as add-on treatment for myasthenia gravis. Stakeholders from academia, a patient organization, the Dutch National Health Care Institute (NHCI) and Dutch Medicines Evaluation Board (MEB) advised on the trial design. The NHCI and MEB agreed to provide scientific advice on the suitability of the evidence generated by the trial, for regulatory decisions. This paper describes the feasibility of the trial and the utility of its aggregated results. RESULTS: The trialists experienced the trial as feasible. Retrospective interviews showed that the trial as performed was acceptable to patients. The treatment effect in the primary outcome measure, muscle strength, was statistically significant when inferred to the population level, though the effect size was modest. Secondary outcomes were statistically significant in a preplanned, fixed effects analysis within the four patients. The NHCI advised that it could potentially make reimbursement decisions based on the Fitting Evidence framework, should the trialists decide to apply for reimbursement. The MEB advised that for a licensing decision, the N-of-1 design is a last-resort option for demonstrating treatment benefit in a rare disease. N-of-1 trials alone do not provide enough evidence on potential risk. The MEB found the current trial inconclusive. It suggested doing a 2-armed trial of longer duration, possibly with a different outcome measure (postponement of corticosteroid use). It suggested engaging a consultancy or commercial sponsor, should the trialists decide to seek market authorization of the drug. CONCLUSIONS: In theory, evidence from aggregated N-of-1 trials is suitable for use in licensing and reimbursement decisions. The current example illustrates differences in interpretation of N-of-1 results by health authorities. In the era of personalized medicine, consensus is required on the interpretation of data from study designs geared to small groups. Demonstrating effectiveness of inexpensive medicines in small populations may require involvement of non-commercial parties, to preserve affordability.

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.

Ephedrine treatment for autoimmune myasthenia gravis.

We studied the effect and safety of ephedrine as add-on treatment for patients with myasthenia gravis with acetylcholine receptor antibodies (AChR MG), who do not sufficiently respond to standard treatment. Four patients with AChR MG were included in a placebo-controlled, double-blind, and randomised, multiple crossover series of n-of-1 trials. Each n-of-1 trial consisted of 3 cycles, in which two 5-day intervention periods were followed by 2 days washout. In each cycle, ephedrine 50 mg daily in 2 doses was compared with placebo in the alternate treatment period. Primary outcome was a change in QMG score. Add-on treatment with ephedrine compared with placebo improved QMG score by 1.0 point (95% confidence interval 0.21-1.79), which was significant for the group of trial patients as well as for the population treatment effect. Ephedrine also showed a significant trial average treatment effect for all secondary outcomes, improving MG Composite by 2.7, MG-ADL by 1.0 and VAS score for muscle strength by 1.1. Adverse events were mild and included palpitations, tremor and restlessness. Although all ECGs were normal, ephedrine prolonged the corrected QT interval. Ephedrine as add-on treatment for myasthenia gravis resulted in a small but consistent reduction of symptoms and weakness in patients with moderate disease severity.

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.