Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases.

For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient's data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe

Solving unsolved rare neurological diseases-a Solve-RD viewpoint.

Funder: Durch Princess Beatrix Muscle Fund Durch Speeren voor Spieren Muscle FundFunder: University of Tübingen Medical Faculty PATE programFunder: European Reference Network for Rare Neurological Diseases | 739510Funder: European Joint Program on Rare Diseases (EJP-RD COFUND-EJP) | 44140962

Twist exome capture allows for lower average sequence coverage in clinical exome sequencing

Background Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main determinant for the sensitivity to detect single-nucleotide (SNVs) and copy number variants (CNVs). Here we compared the ability to obtain comprehensive exome coverage for recent exome capture kits and genome sequencing techniques. Results We compared three different widely used enrichment kits (Agilent SureSelect Human All Exon V5, Agilent SureSelect Human All Exon V7 and Twist Bioscience) as well as short-read and long-read WGS. We show that the Twist exome capture significantly improves complete coverage and coverage uniformity across coding regions compared to other exome capture kits. Twist performance is comparable to that of both short- and long-read whole genome sequencing. Additionally, we show that even at a reduced average coverage of 70× there is only minimal loss in sensitivity for SNV and CNV detection. Conclusion We conclude that exome sequencing with Twist represents a significant improvement and could be performed at lower sequence coverage compared to other exome capture techniques

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Le son donné. Une fabrique archivistique

Cet article aborde les spécificités et usages de données sonores produites dans le cadre particulier d’une expérimentation menée à Bruxelles depuis une vingtaine d’années par l’organisation BNA-BBOT. Sur la base d’une pratique transversale mêlant méthodologies et champs d’application divers (art, sciences humaines, éducation), l’auteure expose les modalités et processus singuliers de fabrication, de conservation et d’exploitation de ces données sonores. Ces processus sont ici mis en dialogue avec les enjeux de narrativité, d’historisation et d’appropriation qui leur sont intrinsèquement liés. Entre microrécits et narrations collectives, collection vocale et paysages sonores, une base de données restitue l’épaisseur de ce qui est donné par le son.This article deals with the specificities and uses of sound data produced in the particular context of an experiment led in Brussels over the last twenty years by the BNA-BBOT organization. Relying on a transversal practice mixing methodologies and fields of application (art, human sciences, education), the author exposes the singular modalities and processes of production, conservation and exploitation of these data. These processes are intrinsically linked to issues of narrativity, historization and appropriation. Between micro-stories and collective storytelling, vocal collection and soundscapes, a database renders the thickness of what is given through sound

Instruments pour élaborer une politique à l'égard des populations d'origine ou de nationalité étrangère en Communauté française de Belgique

info:eu-repo/semantics/nonPublishe

Long-term aqueous alteration kinetics of an alpha-doped SON68 borosilicate glass

Fission products and minor actinides are currently immobilized by vitrification in a borosilicate glass known as 'R7T7'. One of the major functions of the glass matrix is to retain the radioactive elements in the event of water intrusion in the geological disposal, expected after several thousand years. The alteration of SON68 glass (nonradioactive surrogate of R7T7 glass) has been extensively studied during the last thirty years and the key mechanisms and kinetics of borosilicate glass alteration have been determined [1]: the first step corresponds to a congruent dissolution characterized by the initial dissolution rate. Then in-situ. recondensation of dissolved species results in the formation of a gel that decreases the alteration rate by several orders of magnitude to a residual alteration rate. The present work focuses on the study of the effects of electronic dose rate, which would induce electronic excitations and ionisations, on this residual alteration rate by studying a beta-doped glass containing 99Tc. Moreover, the behaviour of a long-life isotope, 99Tc (T1/2 = 2.1×105 years), which contributes to the long-term R7T7 glass activity, is considered. A 0.16%wt 99Tc-doped SON68 borosilicate glass is leached here under static conditions, in argon atmosphere at 90°C and at a high surface-area-to-volume ratio (initial S/V = 25 cm-1), in order to reach quickly the residual alteration rate. In addition, a reference experiment is performed by leaching a non-radioactive SON68 borosilicate glass in the same conditions (initial S/V = 26 cm-1, 90°C), but outside the shielded cell. The alteration rate is monitored by the releases of glass alteration tracer elements (B, Na and Li), which are measured by ICP-AES. Most of the leachate samples are analyzed directly. The last sampling is filtered (0.45 µm) and ultrafiltered (10 000 Dalton) to check for colloids. The releases in solution are expressed in terms of normalized mass losses (NL in g.m-2) [2]. Radiation effects on the glass leached and its gel network are characterised on raw grains by Scanning Electron Microscopy (SEM) analyses, and on ground altered glass powder by Transmission Electron Microscopy (TEM) analyses. Technetium releases are also measured by radiometry and its chemical oxidation state is assessed by measuring both pH and redox potential of the leachate. Results do not highlight any significant effect of beta irradiation on the residual alteration stage of this doped glass: similar results have been observed on the reference experiment. These observations are consistent with SEM and TEM characterizations, which show that a protective layer can be formed under beta irradiation. Concerning the behaviour of technetium, as described in figure 1, congruence between boron and technetium releases is observed, traducing the predominance of Tc(VII) in solution under these conditions (Eh = 380 mV/SHE, pH = 8 - 8,5)

Long-term aqueous alteration kinetics of an alpha-doped SON68 borosilicate glass

The long-term behavior of nuclear glass subjected to alpha radiation by minor actinides must be investigated with a view to geological disposal. This study focuses on the effect of alpha radiation on the chemical reactivity of R7T7 glass with pure water, mainly on the residual alteration rate regime. A glass specimen doped with 0.85 wt% 239PuO2 (α emitter) is leached under static conditions in argon atmosphere at 90°C and at a high surface-area-to-volume ratio (S/V = 20 cm-1). The alteration rate is monitored by the release of glass alteration tracer elements (B, Na and Li). Radiation effects on the leached glass and its gel network are characterized by SEM and TEM analyses. Plutonium release is also measured by radiometry and its chemical oxidation state is assessed by measuring the pH and redox potential of the leachates. The results do not highlight any significant effect of alpha radiation on the residual alteration of this doped glass. This observation is consistent with SEM and TEM characterizations, which show that a protective layer can be formed under alpha radiation. Very low concentrations of soluble plutonium are measured in the leachate. These Pu releases are three orders of magnitude lower than the boron release, indicating strong plutonium retention.JRC.E.3-Materials researc