The sixth international RASopathies symposium: Precision medicine—From promise to practice

The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS‐mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life‐limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion

HSPG-Deficient Zebrafish Uncovers Dental Aspect of Multiple Osteochondromas

Multiple Osteochondromas (MO; previously known as multiple hereditary exostosis) is an autosomal dominant genetic condition that is characterized by the formation of cartilaginous bone tumours (osteochondromas) at multiple sites in the skeleton, secondary bursa formation and impingement of nerves, tendons and vessels, bone curving, and short stature. MO is also known to be associated with arthritis, general pain, scarring and occasional malignant transformation of osteochondroma into secondary peripheral chondrosarcoma. MO patients present additional complains but the relevance of those in relation to the syndromal background needs validation. Mutations in two enzymes that are required during heparan sulphate synthesis (EXT1 or EXT2) are known to cause MO. Previously, we have used zebrafish which harbour mutations in ext2 as a model for MO and shown that ext2−/− fish have skeletal defects that resemble those seen in osteochondromas. Here we analyse dental defects present in ext2−/− fish. Histological analysis reveals that ext2−/− fish have very severe defects associated with the formation and the morphology of teeth. At 5 days post fertilization 100% of ext2−/− fish have a single tooth at the end of the 5th pharyngeal arch, whereas wild-type fish develop three teeth, located in the middle of the pharyngeal arch. ext2−/− teeth have abnormal morphology (they were shorter and thicker than in the WT) and patchy ossification at the tooth base. Deformities such as split crowns and enamel lesions were found in 20% of ext2+/− adults. The tooth morphology in ext2−/− was partially rescued by FGF8 administered locally (bead implants). Our findings from zebrafish model were validated in a dental survey that was conducted with assistance of the MHE Research Foundation. The presence of the malformed and/or displaced teeth with abnormal enamel was declared by half of the respondents indicating that MO might indeed be also associated with dental problems

Chromosome microarray analysis as first-line test in pregnancies with a priori low risk for detection of submicroscopic chromosomal abnormalities

n this study, we aimed to explore the utility of chromosomal microarray analysis (CMA) in groups of pregnancies with a priori low risk for detection of submicroscopic chromosome abnormalities, usually not considered an indication for testing, in order to assess whether CMA improves the detection rate of prenatal chromosomal aberrations. A total of 3000 prenatal samples were processed in parallel using both whole-genome CMA and conventional karyotyping. The indications for prenatal testing included: advanced maternal age, maternal serum screening test abnormality, abnormal ultrasound findings, known abnormal fetal karyotype, parental anxiety, family history of a genetic condition and cell culture failure. The use of CMA resulted in an increased detection rate regardless of the indication for analysis. This was evident in high risk groups (abnormal ultrasound findings and abnormal fetal karyotype), in which the percentage of detection was 5.8% (7/120), and also in low risk groups, such as advanced maternal age (6/1118, 0.5%), and parental anxiety (11/1674, 0.7%). A total of 24 (0.8%) fetal conditions would have remained undiagnosed if only a standard karyotype had been performed. Importantly, 17 (0.6%) of such findings would have otherwise been overlooked if CMA was offered only to high risk pregnancies.The results of this study suggest that more widespread CMA testing of fetuses would result in a higher detection of clinically relevant chromosome abnormalities, even in low risk pregnancies. Our findings provide substantial evidence for the introduction of CMA as a first-line diagnostic test for all pregnant women undergoing invasive prenatal testing, regardless of risk factors

Phenotypic expansion in DDX3X - a common cause of intellectual disability in females

De novo variants in DDX3X account for 1-3% of unexplained intellectual disability (ID) cases and are amongst the most common causes of ID especially in females. Forty-seven patients (44 females, 3 males) have been described. We identified 31 additional individuals carrying 29 unique DDX3X variants, including 30 postnatal individuals with complex clinical presentations of developmental delay or ID, and one fetus with abnormal ultrasound findings. Rare or novel phenotypes observed include respiratory problems, congenital heart disease, skeletal muscle mitochondrial DNA depletion, and late-onset neurologic decline. Our findings expand the spectrum of DNA variants and phenotypes associated with DDX3X disorders

Validation of coupled neutronic / thermal-hydraulic codes for VVER reactors Final report

In recent years, the simulation methods for the safety analysis of nuclear power plants have been continuously improved to perform realistic calculations. Therefore in VALCO work package 2 (WP 2), the usual application of coupled neutron-kinetic / thermal-hydraulic codes to VVER has been supplemented by systematic uncertainty and sensitivity analyses. A comprehensive uncertainty analysis has been carried out. The GRS uncertainty and sensitivity method based on the statistical code package SUSA was applied to the two transients studied earlier in SRR-1/95: A load drop of one turbo-generator in Loviisa-1 (VVER-440), and a switch-off of one feed water pump in Balakovo-4 (VVER-1000). The main steps of these analyses and the results obtained by applying different coupled code systems (SMABRE - HEXTRAN, ATHLET - DYN3D, ATHLET - KIKO3D, ATHLET -BIPR-8) are described in this report. The application of this method is only based on variations of input parameter values. No internal code adjustments are needed. An essential result of the analysis using the GRS SUSA methodology is the identification of the input parameters, such as the secondary-circuit pressure, the control-assembly position (as a function of time), and the control-assembly efficiency, that most sensitively affect safety-relevant output parameters, like reactor power, coolant heat-up, and primary pressure. Uncertainty bands for these output parameters have been derived. The variation of potentially uncertain input parameter values as a consequence of uncertain knowledge can activate system actions causing quite different transient evolutions. This gives indications about possible plant conditions that might be reached from the initiating event assuming only small disturbances. In this way, the uncertainty and sensitivity analysis reveals the spectrum of possible transient evolutions. Deviations of SRR-1/95 coupled code calculations from measurements also led to the objective to separate neutron kinetics from thermal-hydraulic feedback effects. Thus, in VALCO work package 3 (WP 3) stand-alone three-dimensional neutron-kinetic codes have been validated. Measurements carried out in an original-size VVER-1000 mock-up (V-1000 facility, Kurchatov Institute Moscow) were used for the validation of the codes DYN3D, HEXTRAN, KIKO3D and BIPR-8, which are chiefly designed for VVER safety calculations. The significant neutron flux tilt measured in the V-1000 core, which is caused only by radial-reflector asymmetries, was successfully modelled. A good agreement between calculated and measured steady-state powers has been achieved, for relative assembly powers and inner-assembly pin power distributions. Calculated effective multiplication factors exceed unity in all cases. (orig.)European Commision 5th Euratom Framework Programme 1998-2002, Key Action: Nuclear FissionSIGLEAvailable from TIB Hannover: RR 1847(408) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman