Author: "Universitat Duisberg-Essen" - Searchworks@Jio Institute Digital Library Search Results

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16 results on '"Universitat Duisberg-Essen"'

1. Dysregulation of GSK3β-Target Proteins in Skin Fibroblasts of Myotonic Dystrophy Type 1 (DM1) Patients

Author: Geneviève Gourdon, Andreas Hentschel, Hanns Lochmüller, Denisa Hathazi, Valentina Grande, Nikoletta Nikolenko, Ulrike Schara-Schmidt, Theo Marteau, Andreas Roos, Emily O'Connor, Universitat Duisberg-Essen, Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., University of Cambridge School of Clinical Medicine, Université d'Ottawa [Ontario] (uOttawa), Essen University Hospital, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University College London Hospitals (UCLH), University Hospital Freiburg, Barcelona Institute of Science and Technology (BIST), University Children's Hospital of Essen [Essen, Germany], HAL UPMC, Gestionnaire, and Centre de Recherche en Myologie
Subjects: Male, Proteomics, 0301 basic medicine, [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, Medizin, MAP2K2, Muscle Development, CTPS1, CAPN1, 0302 clinical medicine, Myotonic Dystrophy, CTNNB1, Skin, Myogenesis, Kinase, Middle Aged, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Neurology, Female, Adult, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, Myosin light-chain kinase, Protein Serine-Threonine Kinases, Biology, Myotonic dystrophy, Myotonin-Protein Kinase, 03 medical and health sciences, medicine, Humans, Muscle Strength, RNA, Messenger, Protein kinase A, GSK3B, Glycogen Synthase Kinase 3 beta, Gene Expression Profiling, Skeletal muscle, Fibroblasts, medicine.disease, HDAC2, 030104 developmental biology, fibroblast proteomics, GSK3␤, Neurology (clinical), Trinucleotide Repeat Expansion, Biomarkers, 030217 neurology & neurosurgery
Abstract: International audience; Myotonic dystrophy type 1 (DM1) is the most common monogenetic muscular disorder of adulthood. This multisystemic disease is caused by CTG repeat expansion in the 3-untranslated region of the DM1 protein kinase gene called DMPK. DMPK encodes a myosin kinase expressed in skeletal muscle cells and other cellular populations such as smooth muscle cells, neurons and fibroblasts. The resultant expanded (CUG)n RNA transcripts sequester RNA binding factors leading to ubiquitous and persistent splicing deregulation. The accumulation of mutant CUG repeats is linked to increased activity of glycogen synthase kinase 3 beta (GSK3␤), a highly conserved and ubiquitous serine/threonine kinase with functions in pathways regulating inflammation, metabolism, oncogenesis, neurogenesis and myogenesis. As GSK3␤-inhibition ameliorates defects in myogenesis, muscle strength and myotonia in a DM1 mouse model, this kinase represents a key player of DM1 pathobiochemistry and constitutes a promising therapeutic target. To better characterise DM1 patients, and monitor treatment responses, we aimed to define a set of robust disease and severity markers linked to GSK3␤by unbiased proteomic profiling utilizing fibroblasts derived from DM1 patients with low (80-150) and high (2600-3600) CTG-repeats. Apart from GSK3␤ increase, we identified dysregulation of nine proteins (CAPN1, CTNNB1, CTPS1, DNMT1, HDAC2, HNRNPH3, MAP2K2, NR3C1, VDAC2) modulated by GSK3␤. In silico-based expression studies confirmed expression in neuronal and skeletal muscle cells and revealed a relatively elevated abundance in fibroblasts. The potential impact of each marker in the myopathology of DM1 is discussed based on respective function to inform potential uses as severity markers or for monitoring GSK3␤ inhibitor treatment responses.
Published: 2021

2. A<scp>BBS1SVA</scp>F retrotransposon insertion is a frequent cause of<scp>Bardet‐Biedl</scp>syndrome

Author: Corinne Stoetzel, Richard Redon, Erica E. Davis, Véronique Geoffroy, Jean-Louis Mandel, Georgios Kellaris, Samuel Nicaise, Joakim Klar, Clarisse Delvallée, Anne Sophie Leuvrey, Florence Demurger, Manuela Antin, Emmanuelle Génin, Boris Keren, Nicholas Katsanis, Niklas Dahl, Sophie Scheidecker, Elsa Nourisson, Jean Muller, Hélène Dollfus, Jean-François Deleuze, Christel Depienne, Michèle Mathieu-Dramard, Christine Poitou-Bernert, Carmen C. Leitch, Koenraad Devriendt, Sylvie Odent, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Ann & Robert H. Lurie Children's Hospital of Chicago, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Uppsala University, Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Université de Nantes (UN), Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Center for Human Genetics, University of Leuven School of Medicine, SCHOOL of MEDICINE [Louvain], Université Catholique de Louvain = Catholic University of Louvain (UCL)-Université Catholique de Louvain = Catholic University of Louvain (UCL), CHU Amiens-Picardie, Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Northwestern University Feinberg School of Medicine, Agence Nationale de la Recherche, Grant/Award Number: Les Espoirs de l'Université de Strasbourg 2018, CREGEMES, Grant/Award Number: WGS 2016, Fondation pour la Recherche Médicale, Grant/Award Number: ECO20170637509, US National Institutes of Health grants, Grant/Award Numbers: DK072301, GM121317, HD042601, Chard-Hutchinson, Xavier, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: Male, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Retroelements, BBS1, [SDV]Life Sciences [q-bio], Population, Medizin, 030105 genetics & heredity, Biology, Article, Cohort Studies, 03 medical and health sciences, Exon, Gene Frequency, Bardet–Biedl syndrome, Mobile element insertion, Bardet-Biedl syndrome, Genetics, medicine, Humans, Allele, SVA F, education, Genetics (clinical), Medicinsk genetik, education.field_of_study, Whole Genome Sequencing, Polydactyly, medicine.disease, Pedigree, [SDV] Life Sciences [q-bio], Mutagenesis, Insertional, Ciliopathy, founder effect, 030104 developmental biology, Female, Microtubule-Associated Proteins, Medical Genetics, Founder effect
Abstract: International audience; Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment and renal failure. Pathogenic variants in 24 genes account for the molecular basis of >80% of cases. Toward saturated discovery of the mutational basis of the disorder, we carefully explored our cohorts and identified a hominid-specific SINE-R/VNTR/Alu type F (SVA-F) insertion in exon 13 of BBS1 in eight families. In six families, the repeat insertion was found in trans with c.1169 T > G, p.Met390Arg and in two families the insertion was found in addition to other recessive BBS loci. Whole genome sequencing, de novo assembly and SNP array analysis were performed to characterize the genomic event. This insertion is extremely rare in the general population (found in 8 alleles of 8 BBS cases but not in >10 800 control individuals from gnomAD-SV) and due to a founder effect. Its 2435 bp sequence contains hallmarks of LINE1 mediated retrotransposition. Functional studies with patient-derived cell lines confirmed that the BBS1 SVA-F is deleterious as evidenced by a significant depletion of both mRNA and protein levels. Such findings highlight the importance of dedicated bioinformatics pipelines to identify all types of variation.
Published: 2020

3. Variance reduction for Markov chains with application to MCMC

Author: Alexey Naumov, Leonid Iosipoi, Denis Belomestny, Sergey Samsonov, Eric Moulines, Universitat Duisberg-Essen, Vysšaja škola èkonomiki = National Research University Higher School of Economics [Moscow] (HSE), Centre de Mathématiques Appliquées - Ecole Polytechnique (CMAP), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Modélisation en pharmacologie de population (XPOP), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS)-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), and National Research University Higher School of Economics [Moscow] (HSE)
Subjects: FOS: Computer and information sciences, Statistics and Probability, Computer Science - Machine Learning, Machine Learning (stat.ML), Mathematics - Statistics Theory, Statistics Theory (math.ST), 010103 numerical & computational mathematics, Control variates, Statistics - Computation, 01 natural sciences, Machine Learning (cs.LG), Theoretical Computer Science, 010104 statistics & probability, symbols.namesake, [MATH.MATH-ST]Mathematics [math]/Statistics [math.ST], Statistics - Machine Learning, FOS: Mathematics, Sample variance, 0101 mathematics, Computation (stat.CO), Mathematics, Bayes estimator, Markov chain, Probability (math.PR), Markov chain Monte Carlo, Variance (accounting), Delta method, Computational Theory and Mathematics, Mathematik, symbols, Variance reduction, Statistics, Probability and Uncertainty, Algorithm, Mathematics - Probability
Abstract: International audience; In this paper we propose a novel variance reduction approach for additive functionals of Markov chains based on minimization of an estimate for the asymptotic variance of these functionals over suitable classes of control variates. A distinctive feature of the proposed approach is its ability to significantly reduce the overall finite sample variance. This feature is theoretically demonstrated by means of a deep non asymptotic analysis of a variance reduced functional as well as by a thorough simulation study. In particular we apply our method to various MCMC Bayesian estimation problems where it favourably compares to the existing variance reduction approaches.
Published: 2020

4. Trait-based ecology at large scales: Assessing functional trait correlations, phylogenetic constraints and spatial variability using open data

Author: Philippe Usseglio-Polatera, Nikolai Friberg, Jon Webb, Martin Wilkes, Daniel Hering, Lee E. Brown, Francois Edwards, N. LeRoy Poff, Wilco C. E. P. Verberk, Judy England, J. Iwan Jones, John F. Murphy, Coventry University, Centre for Ecology and Hydrology [Wallingford] (CEH), Natural Environment Research Council (NERC), Queen Mary University of London (QMUL), Norwegian Institute for Water Research (NIVA), University of Copenhagen = Københavns Universitet (KU), Universitat Duisberg-Essen, Colorado State University [Fort Collins] (CSU), Laboratoire Interdisciplinaire des Environnements Continentaux (LIEC), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Terre et Environnement de Lorraine (OTELo), Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Radboud university [Nijmegen], School of Geography [Leeds], and University of Leeds
Subjects: 0106 biological sciences, 010504 meteorology & atmospheric sciences, Environmental change, Animal Ecology and Physiology, Biology, 010603 evolutionary biology, 01 natural sciences, Ecology and Environment, Phylogenetics, Environmental Chemistry, Taxonomic rank, Macroecology, ComputingMilieux_MISCELLANEOUS, Ecosystem, Phylogeny, 0105 earth and related environmental sciences, General Environmental Science, Global and Planetary Change, Phylogenetic tree, Ecology, Biodiversity, 15. Life on land, Europe, Phenotype, 13. Climate action, Spatial ecology, Trait, Spatial variability, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, Biologie
Abstract: The growing use of functional traits in ecological research has brought new insights into biodiversity responses to global environmental change. However, further progress depends on overcoming three major challenges involving (a) statistical correlations between traits, (b) phylogenetic constraints on the combination of traits possessed by any single species, and (c) spatial effects on trait structure and trait–environment relationships. Here, we introduce a new framework for quantifying trait correlations, phylogenetic constraints and spatial variability at large scales by combining openly available species’ trait, occurrence and phylogenetic data with gridded, high‐resolution environmental layers and computational modelling. Our approach is suitable for use among a wide range of taxonomic groups inhabiting terrestrial, marine and freshwater habitats. We demonstrate its application using freshwater macroinvertebrate data from 35 countries in Europe. We identified a subset of available macroinvertebrate traits, corresponding to a life‐history model with axes of resistance, resilience and resource use, as relatively unaffected by correlations and phylogenetic constraints. Trait structure responded more consistently to environmental variation than taxonomic structure, regardless of location. A re‐analysis of existing data on macroinvertebrate communities of European alpine streams supported this conclusion, and demonstrated that occurrence‐based functional diversity indices are highly sensitive to the traits included in their calculation. Overall, our findings suggest that the search for quantitative trait–environment relationships using single traits or simple combinations of multiple traits is unlikely to be productive. Instead, there is a need to embrace the value of conceptual frameworks linking community responses to environmental change via traits which correspond to the axes of life‐history models. Through a novel integration of tools and databases, our flexible framework can address this need.
Published: 2020

5. The Macroeconomic Impact of the 1918–19 Influenza Pandemic in Sweden

Author: Martin Karlsson, Mykhailo Matvieiev, Maksym Obrizan, Universitat Duisberg-Essen, Aix-Marseille Sciences Economiques (AMSE), École des hautes études en sciences sociales (EHESS)-Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Université de Kiev, and Kyiv School of economic (KSE)
Subjects: endogenous fertility, Economics and Econometrics, JEL: E - Macroeconomics and Monetary Economics/E.E2 - Consumption, Saving, Production, Investment, Labor Markets, and Informal Economy/E.E2.E21 - Consumption • Saving • Wealth, 1918-19 influenza, overlapping generations models, Wirtschaftswissenschaften, [SHS.ECO]Humanities and Social Sciences/Economics and Finance, JEL: I - Health, Education, and Welfare/I.I1 - Health/I.I1.I15 - Health and Economic Development, epidemics
Abstract: in press What is the economic cost in the medium to long run of an epidemic that kills a large part of the labor force? To answer this question we build an overlapping generations model and calibrate it to the Swedish economy before the 1918–19 influenza pandemic. In the medium run the epidemic, which reduced the population by 0.66%, produces a modest increase in per capita consumption of survivors by 0.45%; however, the benefits are unevenly spread across cohorts. We also find that aggregate labor supply responds elastically while aggregate consumption and investment respond inelastically to the population decline. The aggregate consumption, for example, reduces by 0.27% only for each percentage point decrease in population over the following 10 years. Finally, we document that in the long run, the epidemic has a large cumulative effect over the following century.
Published: 2022

6. Metadata standards and practical guidelines for specimen and DNA curation when building barcode reference libraries for aquatic life

Author: Magali Schweizer, Frederik Leliaert, Jan Pawlowski, Rodolphe Rougerie, Frédéric Rimet, Torbjørn Ekrem, Alexis Canino, Teofana Chonova, David G. Mann, Agnès Bouchez, Régis Lionel Vivien, Christian Chauvin, Chloé Goulon, Valentin Vasselon, Romain Gastineau, Rosa Trobajo, Christophe Laplace-Treyture, Jonas Zimmermann, Eva Aylagas, Wolf-Henning Kusber, Andrzej Witkowski, Vona Méléder, Frédéric Marchand, Sinziana F. Rivera, Maria Kahlert, Muriel Gugger, Filipe O. Costa, Maria Holzmann, Benoît J.D. Ferrari, Serena Rasconi, Alexander M. Weigand, Regine Jahn, Fedor Čiampor, Florian Leese, Ángel Borja, Centre Alpin de Recherche sur les Réseaux Trophiques et Ecosystèmes Limniques (CARRTEL), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), King Abdullah University of Science and Technology (KAUST), Basque Research and Technology Alliance (BRTA), King Abdulaziz University, Ecosystèmes aquatiques et changements globaux (UR EABX), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Slovak Academy of Science [Bratislava] (SAS), Universidade do Minho, Swiss Centre for Applied Ecotoxicology (Ecotox Center), Ecole Polytechnique Fédérale de Lausanne (EPFL), Technical university of Szczecin, Collection des Cyanobactéries, Institut Pasteur [Paris], University of Geneva [Switzerland], Freie Universität Berlin, Swedish University of Agricultural Sciences (SLU), Universitat Duisberg-Essen, Botanic Garden Meise, Institute of Agrifood Research and Technology [Sant Carles de la Ràpita] (IRTA), Institute of Agrifood Research and Technology (IRTA), Royal Botanic Garden Edinburgh, Unité Expérimentale d'Ecologie et d'Ecotoxicologie Aquatique - U3E (Rennes, France) (U3E ), Université de Nantes (UN), Polish Academy of Sciences (PAN), ID-Gene ecodiagnostics [Geneva], Institut de Systématique, Evolution, Biodiversité (ISYEB ), Muséum national d'Histoire naturelle (MNHN)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), Laboratoire de Planétologie et Géodynamique [UMR 6112] (LPG), Université d'Angers (UA)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), SCIMABIO Interface SAS, Musée National d'Histoire Naturelle de Luxembourg (MNHN), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), This paper was written under COST Action DNAqua-Net. The European COST Action DNAqua-Net (CA 15219 collaborative network which gathers several hundreds of scientists and water managers, with the objective of developing new genetic tools for bioassessment and monitoring of aquatic ecosystems (Leese et al. 2016)., European Project, West Pomeranian University of Technology in Szczecin (ZUT), Universidade do Minho = University of Minho [Braga], Université de Genève = University of Geneva (UNIGE), Institut Pasteur [Paris] (IP), Meise Botanic Garden [Belgium] (Plantentuin), Institut de Recerca i Tecnologia Agroalimentàries = Institute of Agrifood Research and Technology (IRTA), Royal Botanic Garden [Edinburgh], Muséum national d'Histoire naturelle (MNHN)-École Pratique des Hautes Études (EPHE), Producció Animal, and Aigües Marines i Continentals
Subjects: 0106 biological sciences, 0301 basic medicine, Computer science, [SDV]Life Sciences [q-bio], Ciências Biológicas [Ciências Naturais], computer.software_genre, Barcode, 01 natural sciences, DNA barcoding, law.invention, law, QH540-549.5, aquatic organisms, media_common, Database, Ecology, Quality, Voucher, Identification (information), Aquatic organisms, quality, Biologie, Traceability, media_common.quotation_subject, reference library, Engenharia e Tecnologia::Engenharia do Ambiente, 010603 evolutionary biology, 03 medical and health sciences, Genetics (medical genetics to be 30107 and agricultural genetics to be 40402), Genetics, Quality (business), Relevance (information retrieval), 14. Life underwater, Molecular Biology, Nature and Landscape Conservation, Engenharia do Ambiente [Engenharia e Tecnologia], Metadata, Ciências Naturais::Ciências Biológicas, metadata, barcode, Reference library, DNA, 030104 developmental biology, traceability, Animal Science and Zoology, computer
Abstract: DNA barcoding and metabarcoding is increasingly used to effectively and precisely assess and monitor biodiversity in aquatic ecosystems. As these methods rely on data availability and quality of barcode reference libraries, it is important to develop and follow best practices to ensure optimal quality and traceability of the metadata associated with the reference barcodes used for identification. Sufficient metadata, as well as vouchers, corresponding to each reference barcode must be available to ensure reliable barcode library curation and, thereby, provide trustworthy baselines for downstream molecular species identification. This document (1) specifies the data and metadata required to ensure the relevance, the accessibility and traceability of DNA barcodes and (2) specifies the recommendations for DNA harvesting and for the storage of both voucher specimens/samples and barcode data, (undefined)
Published: 2021

7. Genetic variants in components of the NALCN–UNC80–UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies)

Author: Peter Bauer, Nuria C. Bramswig, Hartmut Engels, Abdelrahim Abdrabou Sadek, Hasnaa M. Elbendary, Beate Albrecht, Lara Segebrecht, Joseph G. Gleeson, Boris Keren, Diane Doummar, Arndt Rolfs, Jennifer McEvoy-Venneri, Nicole Philip, Christel Depienne, Thomas Wieland, Samira Ismail, Laurent Villard, Tim M. Strom, Michèle Mayer, Aida M. Bertoli-Avella, Maha S. Zaki, Svetlana Gorokhova, Alma Kuechler, Dagmar Wieczorek, Caroline Nava, Nathalie Dorison, André Mégarbané, Amal Alhashem, Stéphanie Valence, Cyril Mignot, Delphine Héron, Valentina Stanley, Isabelle Marey, Nadja Ehmke, Nouriya Al-Sannaa, Hermann-Josef Lüdecke, Sarar Mohamed, Denise Horn, Camille Trautman, Kiely N. James, Katharina Bröhl, Cecile Ravix, Aida I. Al Aqeel, Maissa Bah, Mahmoud Y. Issa, Institut für Humangenetik [Essen], Universitätsklinikum Essen, Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neuropédiatrie [Trousseau], Centre de Génétique Moléculaire et Chromosomique du GH Pitié-Salpêtrière, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Service de génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service de biochimie et de génétique moléculaire [CHU Cochin], CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Pitié-Salpêtrière [APHP], Unité Fonctionnelle de Génétique Médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Centre de Référence des Déficiences Intellectuelles de Causes Rares, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Albrecht-Kossel-Institut fur Neuroregeneration, Universität Rostock, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Institute of Human Genetics, Helmholtz-Zentrum München (HZM)-Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Rheinische Friedrich-Wilhelms-Universität Bonn, Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Laboratory of Neurogenetics, Howard Hughes Medical Institute, Department of Neurosciences, University of California [San Diego] (UC San Diego), University of California-University of California, Universität Duisburg-Essen [Essen], Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Helmholtz Zentrum München = German Research Center for Environmental Health-Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, University of California (UC)-University of California (UC), and Universität Duisburg-Essen = University of Duisburg-Essen [Essen]
Subjects: Adult, Genetic Markers, Male, 0301 basic medicine, Adolescent, Developmental Disabilities, [SDV]Life Sciences [q-bio], Medizin, Disease, Biology, Ion Channels, Sodium Channels, Article, Young Adult, 03 medical and health sciences, Ion channel complex, Genetic variation, Genetics, medicine, Humans, Missense mutation, Child, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), [SDV.GEN]Life Sciences [q-bio]/Genetics, Psychomotor retardation, Infant, Newborn, Genetic Variation, Infant, Membrane Proteins, Phenotype, Hypotonia, Human genetics, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Channelopathies, Female, medicine.symptom, Carrier Proteins
Abstract: NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.
Published: 2018

8. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Author: Florian R. T., Kraft F., Leitao E., Kaya S., Klebe S., Magnin E., van Rootselaar A. -F., Buratti J., Kuhnel T., Schroder C., Giesselmann S., Tschernoster N., Altmueller J., Lamiral A., Keren B., Nava C., Bouteiller D., Forlani S., Jornea L., Kubica R., Ye T., Plassard D., Jost B., Meyer V., Deleuze J. -F., Delpu Y., Avarello M. D. M., Vijfhuizen L. S., Rudolf G., Hirsch E., Kroes T., Reif P. S., Rosenow F., Ganos C., Vidailhet M., Thivard L., Mathieu A., Bourgeron T., Kurth I., Rafehi H., Steenpass L., Horsthemke B., Berkovic S. F., Bisulli F., Brancati F., Canafoglia L., Casari G., Guerrini R., Ishiura H., Licchetta L., Mei D., Pippucci T., Sadleir L., Scheffer I. E., Striano P., Tinuper P., Tsuji S., Zara F., LeGuern E., Klein K. M., Labauge P., Bennett M. F., Bahlo M., Gecz J., Corbett M. A., Tijssen M. A. J., van den Maagdenberg A. M. J. M., Depienne C., Florian, R. T., Kraft, F., Leitao, E., Kaya, S., Klebe, S., Magnin, E., van Rootselaar, A. -F., Buratti, J., Kuhnel, T., Schroder, C., Giesselmann, S., Tschernoster, N., Altmueller, J., Lamiral, A., Keren, B., Nava, C., Bouteiller, D., Forlani, S., Jornea, L., Kubica, R., Ye, T., Plassard, D., Jost, B., Meyer, V., Deleuze, J. -F., Delpu, Y., Avarello, M. D. M., Vijfhuizen, L. S., Rudolf, G., Hirsch, E., Kroes, T., Reif, P. S., Rosenow, F., Ganos, C., Vidailhet, M., Thivard, L., Mathieu, A., Bourgeron, T., Kurth, I., Rafehi, H., Steenpass, L., Horsthemke, B., Berkovic, S. F., Bisulli, F., Brancati, F., Canafoglia, L., Casari, G., Guerrini, R., Ishiura, H., Licchetta, L., Mei, D., Pippucci, T., Sadleir, L., Scheffer, I. E., Striano, P., Tinuper, P., Tsuji, S., Zara, F., Leguern, E., Klein, K. M., Labauge, P., Bennett, M. F., Bahlo, M., Gecz, J., Corbett, M. A., Tijssen, M. A. J., van den Maagdenberg, A. M. J. M., Depienne, C., Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Amsterdam Neuroscience [Pays-Bas], Vrije Universiteit Amsterdam [Amsterdam] (VU)-University of Amsterdam [Amsterdam] (UvA)-VU University Medical Center [Amsterdam], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre for Molecular Medicine Cologne [Cologne] (CMMC), University Hospital of Cologne [Cologne], Cologne Center for Genomics [Cologne] (CCG), University of Cologne, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), genomic vision, Leiden University Medical Center (LUMC), Universiteit Leiden, Centre de référence des épilepsies rares [CHRU Strasbourg] (CRéER), Centre Hospitalier Régional Universitaire de Strasbourg (CHRU de Strasbourg), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, School of Biological Sciences [Adelaïde], University of Adelaide, Goethe-University Frankfurt am Main, Philipps Universität Marburg = Philipps University of Marburg, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne, Epilepsy Research Centre, University of Calgary, Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), South Australian Health and Medical Research Institute [ Adelaide] (SAHMRI), University Medical Center Groningen [Groningen] (UMCG), This study has been financially supported by three different grants from the Fondation Maladies rares to C.D. (2009, 2010, 2016), Assistance Publique des Hôpitaux de Paris (APHP), INSERM, the 'Investissements d’Avenir' programme ANR-10-IAIHU-06 (IHU-A-ICM), University Duisburg-Essen and University Hospital Essen. M.B. was supported by an Australian National Health and Medical Research Council (NHMRC) Program Grant (GNT1054618) and an NHMRC Senior Research Fellowship (GNT1102971). This work was also supported by the Victorian Government’s Operational Infrastructure Support Program and the NHMRC Independent Research Institute Infrastructure Support Scheme (IRIISS). Laura Canafoglia: Member of the European Reference Network on Rare and Complex epilepsies, ERN EpiCARE., We thank the families for their participation in this study, Agnès Rastetter (ICM, Paris, France) for RNA extraction, and Emmanuelle Apartis (Hôpital Saint-Antoine, Paris, France) for electrophysiological assessment of Family 1. DNA extraction and cell culture of lymphoblasts have been performed at the DNA and cell bank of ICM (Paris, France). RNA-seq has been performed on the GenomEast platform of IGBMC, Illkirch, France. WGS has been performed by the Centre National de Recherche en Génomique Humaine (CNRGH) Institut de Biologie François Jacob, Evry, France. We thank Jean-Louis Mandel and Nicolas Charlet-Berguerand (IGBMC, Strasbourg, France), Cécile Cazeneuve (Hôpital Pitié-Salpêtrière, Paris, France), Charles Marcaillou (Integragen, Evry, France) and Isabel Silveira (Porto, Portugal) for valuable discussions., FAME consortium : Berkovic SF, Bisulli F, Brancati F, Canafoglia L, Casari G, Guerrini R, Ishiura H, Licchetta L, Mei D, Pippucci T, Sadleir L, Scheffer IE, Striano P, Tinuper P, Tsuji S, Zara F., Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de Recherche en Génomique Humaine (CNRGH), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), RWTH Aachen University, Universität Duisburg-Essen [Essen], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Philipps University of Marburg, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Rahel T. Florian, Florian Kraft, Elsa Leitão, Sabine Kaya, Stephan Klebe, Eloi Magnin, Anne-Fleur van Rootselaar, Julien Buratti, Theresa Kühnel, Christopher Schröder, Sebastian Giesselmann, Nikolai Tschernoster, Janine Altmueller, Anaide Lamiral, Boris Keren, Caroline Nava, Delphine Bouteiller, Sylvie Forlani, Ludmila Jornea, Regina Kubica, Tao Ye, Damien Plassard, Bernard Jost, Vincent Meyer, Jean-François Deleuze, Yannick Delpu, Mario D.M. Avarello, Lisanne S. Vijfhuizen, Gabrielle Rudolf, Edouard Hirsch, Thessa Kroes, Philipp S. Reif, Felix Rosenow, Christos Ganos, Marie Vidailhet, Lionel Thivard, Alexandre Mathieu, Thomas Bourgeron, Ingo Kurth, Haloom Rafehi, Laura Steenpass, Bernhard Horsthemke, FAME consortium, Eric LeGuern, Karl Martin Klein, Pierre Labauge, Mark F. Bennett, Melanie Bahlo, Jozef Gecz, Mark A. Corbett, Marina A.J. Tijssen, Arn M.J.M. van den Maagdenberg, Christel Depienne, Francesca Bisulli, Laura Licchetta, Paolo Tinuper, MATHIEU, Alexandre, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: Male, MESH: Introns, [SDV]Life Sciences [q-bio], Medizin, MESH: DNA Repeat Expansion, Epilepsies, Myoclonic, [SDV.GEN] Life Sciences [q-bio]/Genetics, MARCH6, expansion, MESH: Ubiquitin-Protein Ligases/genetics, MESH: Aged, MESH: Middle Aged, DNA Repeat Expansion, Neurodegenerative diseases, MESH: Epilepsies, Myoclonic, Chromosome Mapping, Middle Aged, MESH: Epilepsies, Myoclonic/genetics, Pedigree, MESH: Young Adult, Female, ddc:500, MESH: Membrane Proteins, Technology Platforms, Genomic instability, Adult, Adolescent, MESH: Pedigree, Ubiquitin-Protein Ligases, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Familial Adult Myoclonic Epilepsy type 3, Article, Young Adult, Humans, Aged, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Epilepsy, Membrane Proteins, MESH: Adult, MESH: Membrane Proteins/genetics, MESH: Ubiquitin-Protein Ligases, MESH: Male, Introns, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Chromosome Mapping, MESH: Female, Neurological disorders
Abstract: Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements., Familial cortical myoclonic tremor with epilepsy (FAME) is a slowly progressing cortical tremor mapping to various genomic loci, including intronic expansions in SAMD12 for FAME1. Here, Florian et al. describe mixed intronic TTTTA/TTTCA expansions of various lengths in the first intron of MARCH6 as a cause of FAME3.
Published: 2019

9. Full-length de novo viral quasispecies assembly through variation graph construction

Author: Leen Stougie, Johannes Köster, Bastiaan van der Roest, Jasmijn A. Baaijens, Alexander Schönhuth, Centrum Wiskunde & Informatica (CWI), University Medical Center [Utrecht], Universitat Duisberg-Essen, Dana-Farber Cancer Institute [Boston], Vrije Universiteit Amsterdam [Amsterdam] (VU), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Utrecht University [Utrecht], Operations Analytics, Tinbergen Institute, Amsterdam Business Research Institute, and Econometrics and Operations Research
Subjects: Statistics and Probability, Computer science, Contiguity, [SDV]Life Sciences [q-bio], Mutant, Medizin, Viral quasispecies, Computational biology, Genome, Biochemistry, 03 medical and health sciences, Extant taxon, Molecular Biology, 030304 developmental biology, 0303 health sciences, Contig, Minimization problem, 030302 biochemistry & molecular biology, Haplotype, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Computer Science Applications, Computational Mathematics, Quasispecies, Computational Theory and Mathematics, Haplotypes, Simulated data, Graph (abstract data type), Algorithms, Software, Reference genome
Abstract: Motivation Viruses populate their hosts as a viral quasispecies: a collection of genetically related mutant strains. Viral quasispecies assembly is the reconstruction of strain-specific haplotypes from read data, and predicting their relative abundances within the mix of strains is an important step for various treatment-related reasons. Reference genome independent (‘de novo’) approaches have yielded benefits over reference-guided approaches, because reference-induced biases can become overwhelming when dealing with divergent strains. While being very accurate, extant de novo methods only yield rather short contigs. The remaining challenge is to reconstruct full-length haplotypes together with their abundances from such contigs. Results We present Virus-VG as a de novo approach to viral haplotype reconstruction from preassembled contigs. Our method constructs a variation graph from the short input contigs without making use of a reference genome. Then, to obtain paths through the variation graph that reflect the original haplotypes, we solve a minimization problem that yields a selection of maximal-length paths that is, optimal in terms of being compatible with the read coverages computed for the nodes of the variation graph. We output the resulting selection of maximal length paths as the haplotypes, together with their abundances. Benchmarking experiments on challenging simulated and real datasets show significant improvements in assembly contiguity compared to the input contigs, while preserving low error rates compared to the state-of-the-art viral quasispecies assemblers. Availability and implementation Virus-VG is freely available at https://bitbucket.org/jbaaijens/virus-vg. Supplementary information Supplementary data are available at Bioinformatics online.
Published: 2018

10. Mutations in the BAF-complex subunit DPF2 associated with Coffin-Siris syndrome

Author: Andrew O.M. Wilkie, Georgia Vasileiou, Bernt Popp, Yun Li, Maren Wenzel, Marion Gérard, Susan Tomkins, Jenny Morton, Megan T. Cho, André Reis, Astrid Weber, George E. Hoganson, Beate Albrecht, Felix B. Engel, Arif B. Ekici, Maria-Renée Plona, Janine Altmüller, Christian Thiel, Christian Büttner, Jill Clayton-Smith, Karen Low, Dagmar Wieczorek, Deciphering Developmental Disorders Study, Bernd Wollnik, Eduardo Calpena, Nuria C. Bramswig, Sabine Endele, Hermann-Josef Lüdecke, Silvia Vergarajauregui, Tim M. Strom, Institute of Human Genetics, University Erlangen-Nuremberg, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Institut für Humangenetik, Regional Genetic Service, St Mary's Hospital, Manchester, West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Max Planck Institute for Plant Breeding Research (MPIPZ), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), University Medicine Goettingen, Department of Pediatrics [Chicago, IL, USA] (College of Medicine), University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, GeneDx [Gaithersburg, MD, USA], JRC Institute for Energy and Transport (IET), European Commission - Joint Research Centre [Petten], Institut für Humangenetik [Essen], Universitätsklinikum Essen, Technical University of Munich (TUM), Institute of Human Genetics, University Hospital Erlangen, Institute of Human Genetics [Erlangen, Allemagne], Université de Lorraine (UL), Institute of Human Genetics [Cologne], Universitätsklinikum Köln (Uniklinik Köln)-University of Cologne, University Medical Center Göttingen (UMG), Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Technische Universität München [München] (TUM)-German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Birmingham Women's and Children's NHS Foundation Trust, University Hospitals Bristol, Liverpool Women's NHS Foundation Trust, Genetikum, Cologne Center for Genomics [Cologne] (CCG), University of Cologne, Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of Illinois College of Medicine, University of Illinois System, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), and University of Oxford [Oxford]
Subjects: 0301 basic medicine, Male, Medizin, PHD finger, MESH: Amino Acid Sequence, Histones, 0302 clinical medicine, MESH: Child, Chlorocebus aethiops, MESH: Hand Deformities, Congenital, Missense mutation, Coffin-Siris syndrome, histone modification, MESH: Animals, BAF complex, nuclear aggregates, Child, Genetics (clinical), Genetics, MESH: Histones, MESH: Protein Subunits, DNA-Binding Proteins, MESH: COS Cells, Histone, Phenotype, DPF2, MESH: Facies, intellectual disability, Child, Preschool, MESH: HEK293 Cells, COS Cells, Female, MESH: Neck, Hand Deformities, Congenital, MESH: Face, MESH: Abnormalities, Multiple, MESH: Mutation, Adolescent, Protein subunit, Micrognathism, dominant negative, autism spectrum disorder, Biology, MESH: Micrognathism, MESH: Phenotype, Frameshift mutation, MESH: Intellectual Disability, 03 medical and health sciences, Report, medicine, Animals, Humans, Abnormalities, Multiple, Amino Acid Sequence, Gene, Coffin–Siris syndrome, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Coarse facial features, MESH: Child, Preschool, Facies, medicine.disease, MESH: Cercopithecus aethiops, MESH: Male, Protein Subunits, Autism Spectrum Disorder, Baf Complex, Coffin-siris Syndrome, Dominant Negative, Dpf2, Histone Modification, Intellectual Disability, Nail Hypoplasia, Nuclear Aggregates, Phd Finger, 030104 developmental biology, HEK293 Cells, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Face, Mutation, biology.protein, nail hypoplasia, MESH: Female, 030217 neurology & neurosurgery, Neck, MESH: DNA-Binding Proteins, Transcription Factors
Abstract: International audience; Variants affecting the function of different subunits of the BAF chromatin-remodelling complex lead to various neurodevelopmental syndromes, including Coffin-Siris syndrome. Furthermore, variants in proteins containing PHD fingers, motifs recognizing specific histone tail modifications, have been associated with several neurological and developmental-delay disorders. Here, we report eight heterozygous de novo variants (one frameshift, two splice site, and five missense) in the gene encoding the BAF complex subunit double plant homeodomain finger 2 (DPF2). Affected individuals share common clinical features described in individuals with Coffin-Siris syndrome, including coarse facial features, global developmental delay, intellectual disability, speech impairment, and hypoplasia of fingernails and toenails. All variants occur within the highly conserved PHD1 and PHD2 motifs. Moreover, missense variants are situated close to zinc binding sites and are predicted to disrupt these sites. Pull-down assays of recombinant proteins and histone peptides revealed that a subset of the identified missense variants abolish or impaire DPF2 binding to unmodified and modified H3 histone tails. These results suggest an impairment of PHD finger structural integrity and cohesion and most likely an aberrant recognition of histone modifications. Furthermore, the overexpression of these variants in HEK293 and COS7 cell lines was associated with the formation of nuclear aggregates and the recruitment of both wild-type DPF2 and BRG1 to these aggregates. Expression analysis of truncating variants found in the affected individuals indicated that the aberrant transcripts escape nonsense-mediated decay. Altogether, we provide compelling evidence that de novo variants in DPF2 cause Coffin-Siris syndrome and propose a dominant-negative mechanism of pathogenicity.
Published: 2018

11. WDR73 Mutations Cause Infantile Neurodegeneration and Variable Glomerular Kidney Disease

Author: Thomas Müller, Koumudi Godbole, Mirna Assoum, Valérie Delague, Carolin E. Sadowski, Dagmar Wieczorek, Jens-Oliver Steiß, Denny Schanze, Andreas Hahn, Johannes A. Mayr, Berthold Streubel, Friedhelm Hildebrandt, Daniela Prayer, Grazia M.S. Mancini, Martin Zenker, Andreas R. Janecke, Rainer Seidl, Christel Castro, André Mégarbané, M. Imran Khan, Julia Vodopiutz, Nicolas Lévy, Dagmar Csaicsich, Medizinische Universität Wien = Medical University of Vienna, Departement of Pathology, Institute of Food Science and Human Nutrition, Génétique Médicale et Génomique Fonctionnelle (GMGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de génétique médicale, Université Saint-Joseph de Beyrouth (USJ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Division of Clinical Genetics, Innsbruck Medical University [Austria] (IMU), Institute of Human Genetics, University Hospital Magdeburg, Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Medical University of Vienna, Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Institut für Humangenetik [Essen], Universitätsklinikum Essen, Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Saint-Joseph de Beyrouth ( USJ ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Innsbruck Medical University [Austria] ( IMU ), Internal Medicine, and Clinical Genetics
Subjects: Male, Microcephaly, Pathology, Biopsy, DNA Mutational Analysis, Medizin, Cohort Studies, 0302 clinical medicine, Glomerulonephritis, Missense mutation, Child, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Brain, 3. Good health, Galloway Mowat syndrome, Pedigree, Phenotype, Child, Preschool, Heredodegenerative Disorders, Nervous System, Nephrosis, Cerebellar atrophy, Female, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, Molecular Sequence Data, Neuroimaging, Biology, Short stature, Article, 03 medical and health sciences, Young Adult, Atrophy, Internal medicine, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Genetics, medicine, Humans, Amino Acid Sequence, Genetic Association Studies, 030304 developmental biology, Genetic heterogeneity, Proteins, medicine.disease, Endocrinology, Hernia, Hiatal, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Sequence Alignment, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Infantile-onset cerebellar atrophy (CA) is a clinically and genetically heterogeneous trait. Galloway-Mowat syndrome (GMS) is a rare autosomal recessive disease, characterized by microcephaly with brain anomalies including CA in some cases, intellectual disability, and early-infantile-onset nephrotic syndrome. Very recently, WDR73 deficiency was identified as the cause of GMS in five individuals. To evaluate the role of WDR73 mutations as a cause of GMS and other forms of syndromic CA, we performed Sanger or exome sequencing in 51 unrelated patients with CA and variable brain anomalies and in 40 unrelated patients with a diagnosis of GMS. We identified 10 patients from three CA and from two GMS families with WDR73 mutations including the original family described with CA, mental retardation, optic atrophy, and skin abnormalities (CAMOS). There were five novel mutations, of which two were truncating and three were missense mutations affecting highly conserved residues. Individuals carrying homozygous WDR73 mutations mainly presented with a pattern of neurological and neuroimaging findings as well as intellectual disability, while kidney involvement was variable. We document postnatal onset of CA, a retinopathy, basal ganglia degeneration, and short stature as novel features of WDR73-related disease, and define WDR73-related disease as a new entity of infantile neurodegeneration.
Published: 2015

12. EMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver–Russell and Beckwith–Wiedemann syndrome

Author: Thomas Eggermann, Rosanna Weksberg, Frédéric Brioude, Andrea Riccio, David Monk, Gudrun E. Moore, Fiona Macdonald, Karin Buiting, Irène Netchine, Pablo Lapunzina, Thalia Antoniadi, Zeynep Tümer, Matthias Begemann, Eamonn R. Maher, Katja Eggermann, Deborah J G Mackay, Dirk Prawitt, Paolo Lombardi, Elizabeth M. Algar, Jet Bliek, Lukas Soellner, Silvia Russo, Marcel M.A.M. Mannens, Karen Grønskov, Institut für Humangenetik, Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Department of Clinical Genetics, University of Amsterdam [Amsterdam] (UvA), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Genetics and Molecular Pathology Laboratory [Clayton], Monash Health and Hudson Institute, Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Laboratory of Cytogenetics and Molecular Genetics, IRCCS, Department of Clinical Genetics [Copenhagen], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Cancer Epigenetics and Biology Program-PEBC, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Fetal Growth and Developmental Group, University College of London [London] (UCL), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Center for Pediatrics and Adolescent Medicine [Mainz], University Medical Center [Mainz], DISTABiF, Seconda Universita di Napoli, Institute of Genetics and Biophysics, CNR, Naples, Departments of Paediatrics and Molecular Genetics [Toronto], University of Toronto, Division of Clinical and Metabolic Genetics [Toronto], The Hospital for sick children [Toronto] (SickKids), Program in genetics and genome biology, Institute of Medical Science, University of Toronto, INGEMM, Instituto de Genética Médica y Molecular, IDIPAZ-Hospital Universitario La Paz, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), d'Eggis, Gilles, Eggermann, Katja, Bliek, Jet, Brioude, Frédéric, Algar, Elizabeth, Buiting, Karin, Russo, Silvia, Tümer, Zeynep, Monk, David, Moore, Gudrun, Antoniadi, Thalia, Macdonald, Fiona, Netchine, Irène, Lombardi, Paolo, Soellner, Luka, Begemann, Matthia, Prawitt, Dirk, Maher, Eamonn R, Mannens, Marcel, Riccio, Andrea, Weksberg, Rosanna, Lapunzina, Pablo, Grønskov, Karen, Mackay, Deborah JG, Eggermann, Thomas, Maher, Eamonn [0000-0002-6226-6918], Apollo - University of Cambridge Repository, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, and ACS - Amsterdam Cardiovascular Sciences
Subjects: 0301 basic medicine, medicine.medical_specialty, Beckwith-Wiedemann Syndrome, Silver-Russell and Beckwith-Wiedemann syndrome, Best practice, Medizin, Beckwith–Wiedemann syndrome, MEDLINE, 030105 genetics & heredity, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Bioinformatics, Genomic Imprinting, 03 medical and health sciences, medicine, Genetics, Humans, Medical physics, Genetic Testing, Societies, Medical, Genetics (clinical), Genetic testing, Molecular Diagnostic Testing, medicine.diagnostic_test, Chromosomes, Human, Pair 11, Molecular genetic testing, Guideline, medicine.disease, 3. Good health, Europe, Silver-Russell Syndrome, Policy, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Practice Guidelines as Topic, Medical genetics
Abstract: International audience; Molecular genetic testing for the 11p15-associated imprinting disorders Silver–Russell and Beckwith–Wiedemann syndrome (SRS, BWS) is challenging because of the molecular heterogeneity and complexity of the affected imprinted regions. With the growing knowledge on the molecular basis of these disorders and the demand for molecular testing, it turned out that there is an urgent need for a standardized molecular diagnostic testing and reporting strategy. Based on the results from the first external pilot quality assessment schemes organized by the European Molecular Quality Network (EMQN) in 2014 and in context with activities of the European Network of Imprinting Disorders (EUCID.net) towards a consensus in diagnostics and management of SRS and BWS, best practice guidelines have now been developed. Members of institutions working in the field of SRS and BWS diagnostics were invited to comment, and in the light of their feedback amendments were made. The final document was ratified in the course of an EMQN best practice guideline meeting and is in accordance with the general SRS and BWS consensus guidelines, which are in preparation. These guidelines are based on the knowledge acquired from peer-reviewed and published data, as well as observations of the authors in their practice. However, these guidelines can only provide a snapshot of current knowledge at the time of manuscript submission and readers are advised to keep up with the literature.
Published: 2016

13. Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction

Author: I, Parenti, C, Gervasini, J, Pozojevic, K S, Wendt, E, Watrin, J, Azzollini, D, Braunholz, K, Buiting, A, Cereda, H, Engels, L, Garavelli, R, Glazar, B, Graffmann, L, Larizza, H J, Lüdecke, M, Mariani, M, Masciadri, J, Pié, F J, Ramos, S, Russo, A, Selicorni, M, Stefanova, T M, Strom, R, Werner, J, Wierzba, G, Zampino, G, Gillessen-Kaesbach, D, Wieczorek, F J, Kaiser, Cell biology, Università degli Studi di Milano [Milano] (UNIMI), Institut für Humangenetik Lübeck, Universität zu Lübeck [Lübeck], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, IRCCS Istituto Auxologico Italiano, Clinica Pediatrica, Università cattolica del Sacro Cuore [Milano] (Unicatt), Bundesministerium für Bildung und Forschung, ZonMw, Agence Nationale de la Recherche, Society of Pediatric Psychology, FIS PI12-01318, Spain's Ministry of Health-ISCIII, B20, Gobierno de Aragón, SAL31-ID 17292, Accordo Quadro Università-Regione Lombardia, Università degli Studi di Milano = University of Milan (UNIMI), Universität zu Lübeck = University of Lübeck [Lübeck], Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB)
Subjects: Male, Genotype, [SDV]Life Sciences [q-bio], Medizin, Sequence Homology, Genetic Counseling, Severity of Illness Index, Histone Deacetylases, Risk Factors, X Chromosome Inactivation, De Lange Syndrome, Genetics, Humans, Amino Acid Sequence, Child, Genetics (clinical), Cohesin, Sequence Homology, Amino Acid, Base Sequence, Mosaicism, Facies, Sequence Analysis, DNA, DNA, Cornelia de Lange syndrome, Repressor Proteins, Amino Acid, Phenotype, Facial Asymmetry, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, HDAC8, Face, Mutation, X-inactivation, Female, Sequence Analysis
Abstract: International audience; Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous disorder characterized by typical facial dysmorphism, cognitive impairment and multiple congenital anomalies. Approximately 75% of patients carry a variant in one of the five cohesin-related genes NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Herein we report on the clinical and molecular characterization of eleven patients carrying ten distinct variants in HDAC8. Given the high number of variants identified so far, we advise sequencing of HDAC8 as an indispensable part of the routine molecular diagnostic for patients with CdLS or CdLS-overlapping features. The phenotype of our patients is very broad whereas males tend to be more severely affected than females, who instead often present with less canonical CdLS features. The extensive clinical variability observed in the heterozygous females might be at least partially associated with a completely skewed X-inactivation, observed in seven out of eight female patients. Our cohort also includes two affected siblings whose unaffected mother was found to be mosaic for the causative mutation inherited to both affected children. This further supports the urgent need for an integration of highly sensitive sequencing technology to allow an appropriate molecular diagnostic, genetic counselling and risk prediction
Published: 2016

14. Further delineation of the KAT6B molecular and phenotypic spectrum

Author: DDD study, Gannon, Tamsin, Perveen, Rahat, Schlecht, Hélene, Ramsden, Simon, Anderson, Beverley, Kerr, Bronwyn, Day, Ruth, Banka, Siddharth, Suri, Mohnish, Berland, Siren, Gabbett, Michael, Ma, Alan, Lyonnet, Stan, Cormier-Daire, Valerie, Yilmaz, Rüstem, Borck, Guntram, Wieczorek, Dagmar, Anderlid, Britt-Marie, Smithson, Sarah, Vogt, Julie, Moore-Barton, Heather, Simsek-Kiper, Pelin Ozlem, Maystadt, Isabelle, Destrée, Anne, Bucher, Jessica, Angle, Brad, Mohammed, Shehla, Wakeling, Emma, Price, Sue, Singer, Amihood, Sznajer, Yves, Toutain, Annick, Haye, Damien, Newbury-Ecob, Ruth, Fradin, Melanie, McGaughran, Julie, Tuysuz, Beyhan, Tein, Mark, Bouman, Katelijne, Dabir, Tabib, Van den Ende, Jenneke, Luk, Ho Ming, Pilz, Daniela T, Eason, Jacqueline, Davies, Sally, Reardon, Willie, Garavelli, Livia, Zuffardi, Orsetta, Devriendt, Koen, Armstrong, Ruth, Johnson, Diana, Doco-Fenzy, Martine, Bijlsma, Emilia, Unger, Sheila, Veenstra-Knol, Hermine E, Kohlhase, Jürgen, Lo, Ivan FM, Smith, Janine, Clayton-Smith, Jill, Regional Genetic Service, St Mary's Hospital, Manchester, Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Haukeland University Hospital, Royal Brsibane and Womens' Hospital, The University of Queensland, Department of Clinical Genetics, Children’s Hospital at Westmead, Service de génétique médicale, AP-HP Hôpital Necker - Enfants Malades [Paris], Institute of Human Genetics, Universität Ulm, Institut für Humangenetik [Essen], Universitätsklinikum Essen, Karolinska University Hospital, Karolinska University Hospital [Stockholm], University Hospitals Bristol, University of Birmingham [Birmingham], Hacettepe University Children's Hospital, Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Division of Genetics, Birth Defects and Metabolism, Children's hospital of Chicago, Clinical Genetics, Guy's Hospital [London], North West london hospitals NHS Trust, Department of Clinical Genetics, Northampton General Hospital, Northampton, Barzilai Medical Center, Cliniques Universitaires St Luc, Université Catholique de Louvain (UCL), Service de génétique [Tours], Hôpital Bretonneau - CHRU Tours, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1) - Centre National de la Recherche Scientifique (CNRS) - Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique clinique [Rennes], Université de Rennes 1 (UR1) - CHU Pontchaillou [Rennes] - Hôpital Sud, Pediatrics, Istanbul University Cerrahpasa, Birmingham Women’s Hospital, University of Groningen [Groningen], Belfast City Hospital, Centre For Medical Genetics, Clinical Genetic Service, Department of Health, Institute of Medical Genetics, Heath Park, Cardiff, National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin OLCHC, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Dipartimento di Medicina Molecolare, University of Pavia, UZ Leuven - campus Gasthuisberg, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children’s Hospital, Service de Génétique, CHU Reims - Hôpital Maison Blanche - IFR 53, Leiden University Medical Center, Service de Génétique humaine, Université de Lausanne (UNIL), Çocuk Sağlığı ve Hastalıkları, University of Bergen (UiB), Westmead Hospital [Sydney], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universität Ulm - Ulm University [Ulm, Allemagne], Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Cliniques Universitaires Saint-Luc [Bruxelles], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Sheffield Children's NHS Foundation Trust, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Leiden University Medical Center (LUMC), UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Nottingham University Hospitals NHS Trust (NUH), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Università degli Studi di Pavia = University of Pavia (UNIPV), Universiteit Leiden-Universiteit Leiden, Université de Lausanne = University of Lausanne (UNIL), DDD study, and Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)
Subjects: Male, DNA Mutational Analysis, Medizin, Gene Expression, Kidney, Severity of Illness Index, Craniofacial Abnormalities, Missense mutation, Exome, Genetics (clinical), Histone Acetyltransferases, Genetics, OHDO SYNDROME, Patella, Exons, Hypotonia, 3. Good health, Blepharophimosis/diagnosis, Blepharophimosis/genetics, Child, Preschool, Congenital Hypothyroidism/diagnosis, Congenital Hypothyroidism/genetics, Craniofacial Abnormalities/diagnosis, Craniofacial Abnormalities/genetics, Diagnosis, Differential, Facies, Female, Genetic Association Studies, Genotype, Heart Defects, Congenital/diagnosis, Heart Defects, Congenital/genetics, Histone Acetyltransferases/genetics, Humans, Intellectual Disability/diagnosis, Intellectual Disability/genetics, Joint Instability/diagnosis, Joint Instability/genetics, Kidney/abnormalities, Kidney/pathology, Mutation, Patella/abnormalities, Patella/pathology, Phenotype, Psychomotor Disorders/diagnosis, Psychomotor Disorders/genetics, Scrotum/abnormalities, Scrotum/pathology, Urogenital Abnormalities/diagnosis, Urogenital Abnormalities/genetics, Scrotum, Medical genetics, genitopatellar, Say-Barber-Biesecker, medicine.symptom, Psychomotor disorder, Haploinsufficiency, Heart Defects, Congenital, Joint Instability, medicine.medical_specialty, Biology, Blepharophimosis, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, KAT6B, Article, Intellectual Disability, medicine, Congenital Hypothyroidism, CAUSE GENITOPATELLAR SYNDROME, medicine.disease, blepharophimosis, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, DE-NOVO MUTATIONS, Urogenital Abnormalities, Genitopatellar syndrome, HISTONE ACETYLTRANSFERASE KAT6B, Psychomotor Disorders, MENTAL-RETARDATION
Abstract: International audience; KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.
Published: 2015

15. Oto-facial syndrome and esophageal atresia, intellectual disability and zygomatic anomalies - expanding the phenotypes associated with EFTUD2 mutations

Author: Voigt, C., Megarbane, A., Neveling, K., Czeschik, J.C., Albrecht, B., Callewaert, B., Deimling, F. von, Hehr, A., Smeland, M. Falkenberg, Konig, R., Kuechler, A., Marcelis, C., Puiu, M., Reardon, W., Stensland, H.M. Riise, Schweiger, B., Steehouwer, M., Teller, C., Martin, M., Rahmann, S., Hehr, U., Brunner, H.G., Ludecke, H.J., Wieczorek, D., BMC, Ed., Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, Radboud University Medical Center [Nijmegen], Department of Pediatrics and Genetics, Ghent University Hospital-Center for Medical Genetics, Medizinische Genetik, Sozialpädiatrisches Zentrum Coburg, Zentrum für Humangenetik, Universitätsklinikum Regensburg, Department of Medical Genetics, Division of Child and Adolescent Health-University Hospital of North Norway [Tromsø] (UNN), Humangenetik, Universitätsklinikum Frankfurt, Genetica medicala, Victor Babeş University of Medicine and Pharmacy (UMFT), National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin OLCHC, Institut für Diagnostische und Interventionelle Radiologie und Neuroradiologie, Universitätsklinikum Essen, Institut für Humangenetik [Ulm], Universitätsklinikum Ulm - University Hospital of Ulm, Bioinformatics, Computer Science XI, Technische Universität Dortmund [Dortmund] (TU), Abteilung Genominformatik, Universität Duisburg-Essen [Essen]-Institut für Humangenetik, This work was supported by the German Ministry of Education and Research for the CRANIRARE to DW and the FACE consortium to DW and H-JL (BMBF 01GM1211B and 01GM1109B). BC is a postdoctoral research fellow of the fund for scientific research-flanders., and Universität Duisburg-Essen = University of Duisburg-Essen [Essen]-Institut für Humangenetik
Subjects: Adult, Male, Adolescent, Medizin, Oto-facial syndrome with midline malformation, [SDV.GEN] Life Sciences [q-bio]/Genetics, HAPLOINSUFFICIENCY, EFTUD2, Genomic disorders and inherited multi-system disorders [IGMD 3], Young Adult, Oto-facial syndrome with midline malformation, Acrofacial dysostosis type Guion-Almeida (AFDGA), SNRNP, Intellectual Disability, Humans, Genetics(clinical), Pharmacology (medical), Mandibulofacial dysostosis type Guion-Almeida (MFDGA), Child, Esophageal Atresia, Genetic Association Studies, Ribonucleoprotein, U5 Small Nuclear, Medicine(all), Acrofacial dysostosis type Guion-Almeida (AFDGA), [SDV.GEN]Life Sciences [q-bio]/Genetics, COMPLEX, Esophageal atresia (EA), Research, Biology and Life Sciences, Sequence Analysis, DNA, NAGER SYNDROME, Peptide Elongation Factors, Phenotype, Child, Preschool, Mutation, Female, MANDIBULOFACIAL DYSOSTOSIS, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], MENTAL-RETARDATION, Mandibulofacial Dysostosis
Abstract: Contains fulltext : 185259.pdf (Publisher’s version ) (Open Access) BACKGROUND: Mutations in EFTUD2 were proven to cause a very distinct mandibulofacial dysostosis type Guion-Almeida (MFDGA, OMIM #610536). Recently, gross deletions and mutations in EFTUD2 were determined to cause syndromic esophageal atresia (EA), as well. We set forth to find further conditions caused by mutations in the EFTUD2 gene (OMIM *603892). METHODS AND RESULTS: We performed exome sequencing in two familial cases with clinical features overlapping with MFDGA and EA, but which were previously assumed to represent distinct entities, a syndrome with esophageal atresia, hypoplasia of zygomatic complex, microcephaly, cup-shaped ears, congenital heart defect, and intellectual disability in a mother and her two children [AJMG 143A(11):1135-1142, 2007] and a supposedly autosomal recessive oto-facial syndrome with midline malformations in two sisters [AJMG 132(4):398-401, 2005]. While the analysis of our exome data was in progress, a recent publication made EFTUD2 mutations highly likely in these families. This hypothesis could be confirmed with exome as well as with Sanger sequencing. Also, in three further sporadic patients, clinically overlapping to these two families, de novo mutations within EFTUD2 were identified by Sanger sequencing. Our clinical and molecular workup of the patients discloses a broad phenotypic spectrum, and describes for the first time an instance of germline mosaicism for an EFTUD2 mutation. CONCLUSIONS: The clinical features of the eight patients described here further broaden the phenotypic spectrum caused by EFTUD2 mutations or deletions. We here show, that it not only includes mandibulofacial dysostosis type Guion-Almeida, which should be reclassified as an acrofacial dysostosis because of thumb anomalies (present in 12/35 or 34% of patients) and syndromic esophageal atresia [JMG 49(12). 737-746, 2012], but also the two new syndromes, namely oto-facial syndrome with midline malformations published by Megarbane et al. [AJMG 132(4): 398-401, 2005] and the syndrome published by Wieczorek et al. [AJMG 143A(11): 1135-1142, 2007] The finding of mild phenotypic features in the mother of one family that could have been overlooked and the possibility of germline mosaicism in apparently healthy parents in the other family should be taken into account when counseling such families.
Published: 2013

16. Bright ICT: Social Media Analytics for Society and Crisis Management

Author: Stefan Stieglitz, Christian Ehnis, Deborah Bunker, Anthony Sleigh, The University of Sydney Business School, Universitat Duisberg-Essen, Yogesh Dwivedi, Emmanuel Ayaburi, Richard Boateng, John Effah, TC 8, and WG 8.6
Subjects: Kommunikationswissenschaft, Information privacy, Ubiquitous computing, business.industry, [SHS.INFO]Humanities and Social Sciences/Library and information sciences, Crisis management, Engaged scholarship, 05 social sciences, 02 engineering and technology, Public relations, Social media analytics, Information and Communications Technology, ICT, 020204 information systems, 0502 economics and business, 0202 electrical engineering, electronic engineering, information engineering, Information system, [INFO]Computer Science [cs], Social media, Business, 050203 business & management
Abstract: Part 5: Social Media and Open Computing; International audience; Bright ICT promises a new era of IT adoption and use, however, in this current era of ubiquitous computing and social media platforms, we have witnessed IS users being rendered powerless in the information systems development process and professionally manipulated by large technology companies through the algorithmic structures of social networking platforms. In 1987 Markus & Bjorn-Andersen warned us of the potential of consequences of this situation which are now evident on a daily basis where data privacy is compromised, social media platform content is difficult if not impossible to manage and our political and economic systems are disrupted. This paper outlines an engaged research approach being taken by the RISE_SMA project to develop more innovative theoretical approaches and methods for analysing social media data for the assurance of social cohesion during times of crisis.
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16 results on '"Universitat Duisberg-Essen"'

1. Dysregulation of GSK3β-Target Proteins in Skin Fibroblasts of Myotonic Dystrophy Type 1 (DM1) Patients

2. A<scp>BBS1SVA</scp>F retrotransposon insertion is a frequent cause of<scp>Bardet‐Biedl</scp>syndrome

3. Variance reduction for Markov chains with application to MCMC

4. Trait-based ecology at large scales: Assessing functional trait correlations, phylogenetic constraints and spatial variability using open data

5. The Macroeconomic Impact of the 1918–19 Influenza Pandemic in Sweden

6. Metadata standards and practical guidelines for specimen and DNA curation when building barcode reference libraries for aquatic life

7. Genetic variants in components of the NALCN–UNC80–UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies)

8. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

9. Full-length de novo viral quasispecies assembly through variation graph construction

10. Mutations in the BAF-complex subunit DPF2 associated with Coffin-Siris syndrome

11. WDR73 Mutations Cause Infantile Neurodegeneration and Variable Glomerular Kidney Disease

12. EMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver–Russell and Beckwith–Wiedemann syndrome

13. Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction

14. Further delineation of the KAT6B molecular and phenotypic spectrum

15. Oto-facial syndrome and esophageal atresia, intellectual disability and zygomatic anomalies - expanding the phenotypes associated with EFTUD2 mutations

16. Bright ICT: Social Media Analytics for Society and Crisis Management

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