Clinical utility of polygenic risk scores: a critical 2023 appraisal.

Since their first appearance in the context of schizophrenia and bipolar disorder in 2009, polygenic risk scores (PRSs) have been described for a large number of common complex diseases. However, the clinical utility of PRSs in disease risk assessment or therapeutic decision making is likely limited because PRSs usually only account for the heritable component of a trait and ignore the etiological role of environment and lifestyle. We surveyed the current state of PRSs for various diseases, including breast cancer, diabetes, prostate cancer, coronary artery disease, and Parkinson disease, with an extra focus upon the potential improvement of clinical scores by their combination with PRSs. We observed that the diagnostic and prognostic performance of PRSs alone is consistently low, as expected. Moreover, combining a PRS with a clinical score at best led to moderate improvement of the power of either risk marker. Despite the large number of PRSs reported in the scientific literature, prospective studies of their clinical utility, particularly of the PRS-associated improvement of standard screening or therapeutic procedures, are still rare. In conclusion, the benefit to individual patients or the health care system in general of PRS-based extensions of existing diagnostic or treatment regimens is still difficult to judge.

Twenty-Five Years of Contemplating Genotype-Based Hereditary Hemochromatosis Population Screening.

Hereditary hemochromatosis (HH) is a rather frequent, preventable disease because the progressive iron overload affecting many organs can be effectively reduced by phlebotomy. Even before the discovery of the major gene, HFE, in 1996, hemochromatosis was seen as a candidate for population-wide screening programmes. A US Centers of Disease Control and the National Human Genome Research Institute expert panel convened in 1997 to consider genotype-based HH population-wide screening and decided that the scientific evidence available at that time was insufficient and advised against. In spite of a large number of studies performed within the last 25 years, addressing all aspects of HH natural history, health economics, and social acceptability, no professional body worldwide has reverted this decision, and HH remains a life-threatening condition that often goes undetected at a curable stage.

Carrier detection probabilities for autosomal recessive variants in unrelated and consanguineous couples - an evaluation of the 86 genes of the ACMG 'Tier 3' panel.

Carrier screening for autosomal recessive variants has become a cornerstone of community and public health genetics. While the first carrier screening programs were confined to conditions with relatively high prevalence, and hence well-known carrier frequency, the number of candidate genes has increased greatly since the advent of high-throughput DNA sequencing technologies. The epidemiological database of the ensuing gene panels is mostly sparse, and judgement of their performance is, therefore, anything but straightforward. We therefore derived estimates of the carrier detection probabilities among non-consanguineous and consanguineous couples as expected using the 'Tier 3' carrier screening gene panel recently recommended by the American College of Medical Genetics (ACMG). For non-Finnish Europeans, the respective estimate for unrelated couples equals 0.63%, implying that the ACMG Tier 3 panel accounts for over 90% of the genetic load for autosomal recessive diseases in this population. Among the offspring of first cousins, the corresponding incidence is expected to be tenfold higher, an increase still consistent with previous estimates of the overall risk of birth defects for this type of mating. Our considerations are intended to aid the implementation of carrier screening programs and to provide additional support to reproductive counselling and to obtaining informed consent.

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

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

[Genetic counseling in Germany: development of demand]. / Humangenetische Beratung in Deutschland: Entwicklung der Inanspruchnahme.

BACKGROUND: With the Act on Genetic Testing (GenDG), the German legislator has issued far-reaching regulations for human genetic services, including genetic counseling. This paper presents data on the use of human genetic counseling in the years before and after the entry into force of GenDG in order to provide an informed assessment of the possible effects of the law. MATERIALS AND METHODS: Over a period of 13 years (2005 to 2017), the human genetic counseling services provided within the framework of the statutory health insurance and billable by EBM via the Kassenärztliche associations were recorded via a database query at the Central Institute of the National Association of Statutory Health Insurance Physicians (ZI-KBV) and via individual Kassenärztliche Vereinigungen Deutschlands. For the discussion of the observable development of using genetic counseling and possible future development, additional data on the referral behavior, the waiting times, processing time, and reasons for consultations were extracted from the GenBIn database. RESULTS AND DISCUSSION: Demand for genetic counseling has steadily increased at an average rate of approximately 6% per year since 2009. This increase started well before the enactment of the GenDG and may be attributed to a multiplicity of factors. Change in demand for genetic counseling is characterized by increasing self-referrals and by increasing referrals by specialists other than obstetricians/gynecologists. Waiting times between 2011 and 2016/2017 have increased. While demand has been growing, the number of key service providers, the contracted medical specialists in human genetics, has remained almost constant. It is foreseeable that capacity limits will be reached if both trends continue.

Results from ten years of post-market environmental monitoring of genetically modified MON 810 maize in the European Union.

In European regulations for the deliberate release into the environment of genetically modified organisms (GMO), the objective of General Surveillance in Post-Market Environmental Monitoring is defined as the identification of the occurrence of adverse effects of the GMO or its use which were not anticipated in the environmental risk assessment (ERA). Accompanying the commercial cultivation in the EU of maize event MON 810, General Surveillance was implemented by Monsanto, the authorization holder, on a voluntary basis. We carried out a statistical analysis on the pooled results of ten years of farmer questionnaires, which were a part of this General Surveillance, amounting to 2,627 farmer fields in eight European countries in the period 2006-2015. This analysis did not reveal any unexpected adverse effects associated with the cultivation of MON 810. Results from farmer questionnaires confirmed that the cultivation of MON 810 resulted in a significant reduction in the use of pesticides, efficient protection against the target pests, and healthier, higher yielding crops compared to conventional maize. MON 810 also had reduced susceptibility to disease and pests when compared to conventional maize. Monitoring characteristics related to environment and wildlife revealed no significant differences between MON 810 and conventional maize. Literature searches, that were also conducted as part of General Surveillance, identified a comprehensive set of publications addressing environmental safety as well as food and feed safety aspects of MON 810. None of the publications indicated any adverse effect of MON 810 that was not anticipated in the initial ERA, nor did they lead to a change in the conclusions of the initial risk assessment that demonstrated the safety of MON 810. The development of resistance by the target pests (Ostrinia nubilalis, ECB and Sesamia nonagrioides, MCB) was the only potential adverse effect identified in the ERA of MON 810 cultivation in the EU. The extensive safety data package for MON 810, the robust weight of evidence demonstrating both its safety and benefits, and the history of safe use of MON 810 for 15 years in the EU, indicates that focussing the General Surveillance of MON 810 on literature searches and farmer complaint systems would be appropriately protective. This will allow the identification of potential adverse effect not anticipated in the initial ERA without the intensive effort and organizational challenges of farmer questionnaires.

NGS-Based genetic testing for heritable cardiovascular diseases. Specific requirements for obtaining informed consent.

Clinical genetic testing in cardiovascular genetic medicine has undergone rapid changes. Next generation sequencing allows simultaneous testing of all genes associated with any cardiovascular phenotype, and molecular genetic testing for multiple genes has become the standard of practice for cardiovascular medicine. While technical and clinical advantages of multigenic approaches are evident, informed consent procedures have become more complex and challenging to the physician ordering such a test, particularly due to the increased potential for unsolicited findings. Based on the EuroGentest "Guidelines for diagnostic next-generation sequencing" we here propose a set of disease-specific requirements for obtaining informed consent for NGS-based genetic testing in a cardiogenetic clinic. We can show that it is often not feasible to obtain informed consent for every detail and suggest, in such cases, to reach general consent beforehand and discuss specific implications of unsolicited findings after the test results are available.

Metadata Correction: Conceptualization and Implementation of the Central Information Portal on Rare Diseases: Protocol for a Qualitative Study.

[This corrects the article DOI: 10.2196/resprot.7425.].

Humoral and cellular immune response in Wistar Han RCC rats fed two genetically modified maize MON810 varieties for 90 days (EU 7th Framework Programme project GRACE).

The genetically modified maize event MON810 expresses a Bacillus thuringiensis-derived gene, which encodes the insecticidal protein Cry1Ab to control some lepidopteran insect pests such as the European corn borer. It has been claimed that the immune system may be affected following the oral/intragastric administration of the MON810 maize in various different animal species. In the frame of the EU-funded project GRACE, two 90-day feeding trials, the so-called studies D and E, were performed to analyze the humoral and cellular immune responses of male and female Wistar Han RCC rats fed the MON810 maize. A MON810 maize variety of Monsanto was used in the study D and a MON810 maize variety of Pioneer Hi-Bred was used in the study E. The total as well as the maize protein- and Cry1Ab-serum-specific IgG, IgM, IgA and IgE levels, the proliferative activity of the lymphocytes, the phagocytic activity of the granulocytes and monocytes, the respiratory burst of the phagocytes, a phenotypic analysis of spleen, thymus and lymph node cells as well as the in vitro production of cytokines by spleen cells were analyzed. No specific Cry1Ab immune response was observed in MON810 rats, and anti-maize protein antibody responses were similar in MON810 and control rats. Single parameters were sporadically altered in rats fed the MON810 maize when compared to control rats, but these alterations are considered to be of no immunotoxicological significance.

Conceptualization and Implementation of the Central Information Portal on Rare Diseases: Protocol for a Qualitative Study.

BACKGROUND: Recently, public and political interest has focused on people living with rare diseases and their health concerns. Due to the large number of different types of rare diseases and the sizable number of patients, taking action to improve the life of those affected is gaining importance. In 2013, the federal government of Germany adopted a national action plan for rare diseases, including the call to establish a central information portal on rare diseases (Zentrales Informationsportal über seltene Erkrankungen, ZIPSE). OBJECTIVE: The objective of this study, therefore, was to conduct scientific research on how such a portal must be designed to meet the needs of patients, their families, and medical professionals, and to provide high-quality information for information seekers. METHODS: We chose a 3-step procedure to develop a needs-based prototype of a central information portal. In the first step, we determined the information needs of patients with rare diseases, their relatives, and health care professionals by means of qualitative interviews and their content-analytical evaluation. On the basis of this, we developed the basic structure of the portal. In the second step, we identified quality criteria for websites on rare diseases to ensure that the information linked with ZIPSE meets the quality demands. Therefore, we gathered existing criteria catalogs and discussed them in an expert workshop. In the third step, we implemented and tested the developed prototypical information portal. RESULTS: A portal page was configured and made accessible on the Web. The structure of ZIPSE was based on the findings from 108 qualitative interviews with patients, their relatives, and health care professionals, through which numerous information needs were identified. We placed particularly important areas of information, such as symptoms, therapy, research, and advisory services, on the start page. Moreover, we defined 13 quality criteria, referring to factors such as author information, creation date, and privacy, enabling links with high-quality information. Moreover, 19 users tested all the developed routines based on usability and comprehensibility. Subsequently, we improved the visual presentation of search results and other important search functions. CONCLUSIONS: The implemented information portal, ZIPSE, provides high-quality information on rare diseases from a central point of access. By integrating the targeted groups as well as different experts on medical information during the construction, the website can assure an improved search for information for users. ZIPSE can also serve as a model for other Web-based information systems in the field of rare diseases. REGISTERED REPORT IDENTIFIER: RR1-10.2196/7425.

Paternal inheritance of plastid-encoded transgenes in Petunia hybrida in the greenhouse and under field conditions.

As already demonstrated in greenhouse trials, outcrossing of transgenic plants can be drastically reduced via transgene integration into the plastid. We verified this result in the field with Petunia, for which the highest paternal leakage has been observed. The variety white 115 (W115) served as recipient and Pink Wave (PW) and the transplastomic variant PW T16, encoding the uidA reporter gene, as pollen donor. While manual pollination in the greenhouse led to over 90% hybrids for both crossings, the transgenic donor resulted only in 2% hybrids in the field. Nevertheless paternal leakage was detected in one case which proves that paternal inheritance of plastid-located transgenes is possible under artificial conditions. In the greenhouse, paternal leakage occurred in a frequency comparable to published results. As expected natural pollination reduced the hybrid formation in the field from 90 to 7.6% and the transgenic donor did not result in any hybrid.

Comparative statistical component analysis of transgenic, cyanophycin-producing potatoes in greenhouse and field trials.

Potatoes are a promising system for industrial production of the biopolymer cyanophycin as a second compound in addition to starch. To assess the efficiency in the field, we analysed the stability of the system, specifically its sensitivity to environmental factors. Field and greenhouse trials with transgenic potatoes (two independent events) were carried out for three years. The influence of environmental factors was measured and target compounds in the transgenic plants (cyanophycin, amino acids) were analysed for differences to control plants. Furthermore, non-target parameters (starch content, number, weight and size of tubers) were analysed for equivalence with control plants. The huge amount of data received was handled using modern statistical approaches to model the correlation between influencing environmental factors (year of cultivation, nitrogen fertilization, origin of plants, greenhouse or field cultivation) and key components (starch, amino acids, cyanophycin) and agronomic characteristics. General linear models were used for modelling, and standard effect sizes were applied to compare conventional and genetically modified plants. Altogether, the field trials prove that significant cyanophycin production is possible without reduction of starch content. Non-target compound composition seems to be equivalent under varying environmental conditions. Additionally, a quick test to measure cyanophycin content gives similar results compared to the extensive enzymatic test. This work facilitates the commercial cultivation of cyanophycin potatoes.

Variability of control data and relevance of observed group differences in five oral toxicity studies with genetically modified maize MON810 in rats.

The data of four 90-day feeding trials and a 1-year feeding trial with the genetically modified (GM) maize MON810 in Wistar Han RCC rats performed in the frame of EU-funded project GRACE were analysed. Firstly, the data obtained from the groups having been fed the non-GM maize diets were combined to establish a historical control data set for Wistar Han RCC rats at the animal housing facility (Slovak Medical University, Bratislava, Slovakia). The variability of all parameters is described, and the reference values and ranges have been derived. Secondly, the consistency of statistically significant differences found in the five studies was analysed. In order to do so, the body weight development, organ weight, haematology and clinical biochemistry data were compared between the studies. Based on the historical control data, equivalence ranges for these parameters were defined, and the values measured in the GM maize-fed groups were compared with these equivalence ranges. Thirdly, the (statistical) power of these feeding studies with whole food/feed was assessed and detectable toxicologically relevant group differences were derived. Linear mixed models (LMM) were applied, and standardized effect sizes (SES) were calculated in order to compare different parameters as well as to provide an overall picture of group and study differences at a glance. The comparison of the five feeding trials showed a clear study effect in the control data. It also showed inconsistency both in the frequency of statistically significant differences and in the difference values between control and test groups.

NCAM2 deletion in a boy with macrocephaly and autism: Cause, association or predisposition?

UNLABELLED: We report on an 8-year-old boy with autism spectrum disorder (ASD), speech delay, behavioural problems, disturbed sleep and macrosomia including macrocephaly carrying a microdeletion that contains the entire NCAM2 gene and no other functional genes. Other family members with the microdeletion show a large skull circumference but do not exhibit any symptoms of autism spectrum disorder. Among many ASD-candidate genes, NCAM2 has been assumed to play a pivotal role in the development of ASD because of its function in the outgrowth and bundling of neurites. Our reported case raises the questions whether the NCAM2-deletion is the true cause of the ASD or only a risk factor and whether there might be any connection in NCAM2 with skull-size KEY WORDS: autism spectrum disorder, macrocephaly, neural cell adhesion molecule 2 protein (NCAM2), array comparative genomic hybridization (microarray).

Adopting Quality Criteria for Websites Providing Medical Information About Rare Diseases.

BACKGROUND: The European Union considers diseases to be rare when they affect less than 5 in 10,000 people. It is estimated that there are between 5000 and 8000 different rare diseases. Consistent with this diversity, the quality of information available on the Web varies considerably. Thus, quality criteria for websites about rare diseases are needed. OBJECTIVE: The objective of this study was to generate a catalog of quality criteria suitable for rare diseases. METHODS: First, relevant certificates and quality recommendations for health information websites were identified through a comprehensive Web search. Second, all considered quality criteria of each certification program and catalog were examined, extracted into an overview table, and analyzed by thematic content. Finally, an interdisciplinary expert group verified the relevant quality criteria. RESULTS: We identified 9 quality certificates and criteria catalogs for health information websites with 304 single criteria items. Through this, we aggregated 163 various quality criteria, each assigned to one of the following categories: thematic, technical, service, content, and legal. Finally, a consensus about 13 quality criteria for websites offering medical information on rare diseases was determined. Of these categories, 4 (data protection concept, imprint, creation and updating date, and possibility to contact the website provider) were identified as being the most important for publishing medical information about rare diseases. CONCLUSIONS: The large number of different quality criteria appearing within a relatively small number of criteria catalogs shows that the opinion of what is important in the quality of health information differs. In addition, to define useful quality criteria for websites about rare diseases, which are an essential source of information for many patients, a trade-off is necessary between the high standard of quality criteria for health information websites in general and the limited provision of information about some rare diseases. Finally, transparently presented quality assessments can help people to find reliable information and to assess its quality.