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5,181 results on '"Seattle Children’s Research Institute"'

1. Age De-escalation Safety Trial of PfSPZ-LARC2 Vaccine in Burkina Faso

Author: University of Maryland, Baltimore, Groupe de Recherche Action en Sante, and Seattle Children's Research Institute
Published: 2024

2. Post Operative Pain Control After Pediatric Hip Surgery

Author: Seattle Children's Research Institute Center for Clinical and Translational Research and David Liston, Assistant Professor, Attending Anesthesiologist
Published: 2021

3. Evidence for gene???gene epistatic interactions among susceptibility loci for systemic lupus erythematosus

Author: University of Michigan and Ann Arbor VA Medical Center, Ann Arbor, University of Puerto Rico, San Juan, Puerto Rico, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, and Oklahoma City VA Medical Center, Oklahoma City, Wake Forest University Health Sciences Center, Winston???Salem, North Carolina, University of Alabama at Birmingham, Northwestern University Feinberg School of Medicine, Chicago, Illinois, Johns Hopkins University School of Medicine, Baltimore, Maryland, University of Colorado Denver School of Medicine, Aurora, University of Washington and Seattle Children's Research Institute, Seattle, University of Texas Health Science Center at Houston, Instituto de Parasitolog??a y Biomedicina L??pez???Neyra, CSIC, Granada, Spain, University of Chicago, Chicago, Illinois, Medical University of South Carolina, Charleston, University of California, San Francisco, Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City, University of Southern California, Los Angeles, University of California, Los Angeles, King's College London and Guy's Hospital, London, UK, Cincinnati Children's Hospital Medical Center and Cincinnati VA Medical Center, Cincinnati, Ohio, Center for Genomics and Oncological Research Pfizer???University of Granada???Junta de Andalucia, Granada, Spain, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, MS#24, Oklahoma City, OK 73104, Hughes, Travis, Adler, Adam, Kelly, Jennifer A., Kaufman, Kenneth M., Williams, Adrienne H., Langefeld, Carl D., Brown, Elizabeth E., Alarc??n, Graciela S., Kimberly, Robert P., Edberg, Jeffrey C., Ramsey???goldman, Rosalind, Petri, Michelle, Boackle, Susan A., Stevens, Anne M., Reveille, John D., Sanchez, Elena, Mart??n, Javier, Niewold, Timothy B., Vil??, Luis M., Scofield, R. Hal, Gilkeson, Gary S., Gaffney, Patrick M., Criswell, Lindsey A., Moser, Kathy L., Merrill, Joan T., Jacob, Chaim O., Tsao, Betty P., James, Judith A., Vyse, Timothy J., Alarc??n???riquelme, Marta E., Harley, John B., Richardson, Bruce C., Sawalha, Amr H., University of Michigan and Ann Arbor VA Medical Center, Ann Arbor, University of Puerto Rico, San Juan, Puerto Rico, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, and Oklahoma City VA Medical Center, Oklahoma City, Wake Forest University Health Sciences Center, Winston???Salem, North Carolina, University of Alabama at Birmingham, Northwestern University Feinberg School of Medicine, Chicago, Illinois, Johns Hopkins University School of Medicine, Baltimore, Maryland, University of Colorado Denver School of Medicine, Aurora, University of Washington and Seattle Children's Research Institute, Seattle, University of Texas Health Science Center at Houston, Instituto de Parasitolog??a y Biomedicina L??pez???Neyra, CSIC, Granada, Spain, University of Chicago, Chicago, Illinois, Medical University of South Carolina, Charleston, University of California, San Francisco, Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City, University of Southern California, Los Angeles, University of California, Los Angeles, King's College London and Guy's Hospital, London, UK, Cincinnati Children's Hospital Medical Center and Cincinnati VA Medical Center, Cincinnati, Ohio, Center for Genomics and Oncological Research Pfizer???University of Granada???Junta de Andalucia, Granada, Spain, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, MS#24, Oklahoma City, OK 73104, Hughes, Travis, Adler, Adam, Kelly, Jennifer A., Kaufman, Kenneth M., Williams, Adrienne H., Langefeld, Carl D., Brown, Elizabeth E., Alarc??n, Graciela S., Kimberly, Robert P., Edberg, Jeffrey C., Ramsey???goldman, Rosalind, Petri, Michelle, Boackle, Susan A., Stevens, Anne M., Reveille, John D., Sanchez, Elena, Mart??n, Javier, Niewold, Timothy B., Vil??, Luis M., Scofield, R. Hal, Gilkeson, Gary S., Gaffney, Patrick M., Criswell, Lindsey A., Moser, Kathy L., Merrill, Joan T., Jacob, Chaim O., Tsao, Betty P., James, Judith A., Vyse, Timothy J., Alarc??n???riquelme, Marta E., Harley, John B., Richardson, Bruce C., and Sawalha, Amr H.
Abstract: Objective Several confirmed genetic susceptibility loci for lupus have been described. To date, no clear evidence for genetic epistasis in lupus has been established. The aim of this study was to test for gene???gene interactions in a number of known lupus susceptibility loci. Methods Eighteen single???nucleotide polymorphisms tagging independent and confirmed lupus susceptibility loci were genotyped in a set of 4,248 patients with lupus and 3,818 normal healthy control subjects of European descent. Epistasis was tested by a 2???step approach using both parametric and nonparametric methods. The false discovery rate (FDR) method was used to correct for multiple testing. Results We detected and confirmed gene???gene interactions between the HLA region and CTLA4 , IRF5 , and ITGAM and between PDCD1 and IL21 in patients with lupus. The most significant interaction detected by parametric analysis was between rs3131379 in the HLA region and rs231775 in CTLA4 (interaction odds ratio 1.19, Z = 3.95, P = 7.8 ?? 10 ???5 [FDR ???0.05], P for multifactor dimensionality reduction = 5.9 ?? 10 ???45 ). Importantly, our data suggest that in patients with lupus, the presence of the HLA lupus risk alleles in rs1270942 and rs3131379 increases the odds of also carrying the lupus risk allele in IRF5 (rs2070197) by 17% and 16%, respectively ( P = 0.0028 and P = 0.0047, respectively). Conclusion We provide evidence for gene???gene epistasis in systemic lupus erythematosus. These findings support a role for genetic interaction contributing to the complexity of lupus heritability.
Published: 2012

4. Check Yourself v2.0

Author: Carolyn McCarty, Research Associate Professor of Pediatrics, University of Washington and Investigator, Seattle Children's Research Institute
Published: 2020

5. Genetic mapping of molar size relations identifies inhibitory locus for third molars in mice

Author: Nicolas Navarro, A. Murat Maga, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Biogéosciences [UMR 6282] [Dijon] (BGS), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Division of Craniofacial Medicine, University of Washington [Seattle], Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, and Study supported partially by NIH/NIDCR Independence to Pathway Award, as well as a Seattle Children’s Research Institute seed fund, and by the National Institute of General Medical Sciences of the National Institutes of Health under grant number P41 GM103545-17.
Subjects: Male, 0106 biological sciences, 0301 basic medicine, Molar, Quantitative Trait Loci, Locus (genetics), Biology, Quantitative trait locus, Inhibitory postsynaptic potential, 010603 evolutionary biology, 01 natural sciences, Article, Mice, 03 medical and health sciences, Quantitative Trait, Heritable, stomatognathic system, Gene mapping, Disease patterns, Genetic variation, Genetics, Animals, Gene, Genetic Association Studies, Genetics (clinical), Chromosome Mapping, Genetic Variation, [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis, Models, Theoretical, Biological Evolution, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 030104 developmental biology, Evolutionary biology, Female, Molar, Third, Lod Score, Algorithms
Abstract: 11 pages; International audience; Molar size in Mammals shows considerable disparity and exhibits variation similar to that predicted by the Inhibitory Cascade model. The importance of such developmental systems in favoring evolutionary trajectories is also underlined by the fact that this model can predict macroevolutionary patterns. Using backcross mice, we mapped QTL for molar sizes controlling for their sequential development. Genetic controls for upper and lower molars appear somewhat similar, and regions containing genes implied in dental defects drive this variation. We mapped three relationship QTLs (rQTL) modifying the control of the mesial molars on the focal third molar. These regions overlap Shh, Sostdc1, and Fst genes, which have pervasive roles in development and should be buffered against new variation. It has theoretically been shown that rQTL produces new variation channeled in the direction of adaptive changes. Our results provide evidence that evolutionary/disease patterns of tooth size variation could result from such a non-random generating process.
Published: 2018

6. Check Yourself Study

Author: Laura Richardson, Professor of Pediatrics, University of Washington and Investigator, Seattle Children's Research Institute
Published: 2018

7. Caractérisation clinique et génétique d’une nouvelle dysplasie ectodermique en mosaïque

Author: Odile Boute, J.-B. Rivière, C. Gondry, Laurence Faivre, Pierre Vabres, S.S. Kholmanskikh, M. E. Ross, B. Devauchelle, B. Demeer, J. St-Onge, David Geneviève, William B. Dobyns, Laurent Guibaud, Julien Thevenon, G. Captier, G. Bernard, E. Carmi, Paul Kuentz, Yannis Duffourd, Alain Bron, Jean-Benoît Courcet, A. Lafon, V. Carmignac, Arthur Sorlin, Didier Bessis, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Weill Cornell Medicine, CHU Amiens-Picardie, McGill University = Université McGill [Montréal, Canada], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Centre Hospitalier Universitaire de Lille (CHU de Lille), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Seattle Children’s Research Institute, Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Service de Dermatologie (CHU de Dijon), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Department of Neurology and Feil Family Brain and Mind Research Institute [New-York] (BMRI), Weill Medical College of Cornell University [New York], Center for neurogenetics [Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York], Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], McGill University Health Center [Montreal] (MUHC), Génétique biologique histologie [CHRU de Besançon], Département de dermatologie [CHU de Montpellier], Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Ophtalmologie (CHU de Dijon), Département Chirurgie Pédiatrique [CHRU Montpellier], Pôle Femme Mère Enfant [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de dermatologie [CHU d'Amiens-Picardie], Département de chirurgie maxillofaciale et stomatologie [CHU d'Amiens-Picardie], Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Radiologie [Amiens], Service d’imagerie pédiatrique et fœtale [Hôpital Femme Mère Enfant - HCL], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service Chirurgie Maxillo-Faciale - Stomatologie - Chirurgie Plastique Réparatrice et Esthétique - Chirurgie de la main (CHU de Dijon), Center for Integrative Brain Research, University of Washington [Seattle], Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), FHU TRANSLAD, Department of Neurology and Feil Family Brain and Mind Research Institute [New-York] ( BMRI ), The Research Institute of the McGill University Health Centre [Montréal, QC, Canada], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Centre Hospitalier Universitaire de Montpellier ( CHU Montpellier ), Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Département de chirurgie infantile [CHRU de Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Hôpital Femme Mère Enfant [CHU - HCL] ( HFME ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), University of Washington [Seattle]-Seattle Children's Research Institute, and McGill University
Subjects: hypomélanose d'ito, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, mosaïcisme, dysplasie ectodermique, Hypomélanose d’Ito, Dermatology, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 3. Good health
Abstract: National audience; Introduction L’hypomélanose d’Ito est définie par l’association d’une hypopigmentation qui suit les lignes de Blaschko et de manifestations principalement neurologiques. Les autres atteintes associées sont variables. Elle peut être associée à diverses anomalies chromosomiques en mosaïque ou à des mutations MTOR lorsqu’elle s’associe à une hémimégalencéphalie. Nous rapportons un nouveau syndrome clinique avec hypomélanose d’Ito et atteinte neuroectodermique en lien avec des mutations postzygotiques de RHOA . Matériel et méthodes Dans le cadre de la cohorte Mosaic Unknown Skin Traits And Related Disorders (MUSTARD), nous avons étudié 5 patients par séquençage haut débit de l’exome complet ou ciblé, sur peau atteinte et dans le sang. Observations Les 5 patients, non apparentés, présentaient tous une hypopigmentation ou une hypotrichose linéaire, associée à une atteinte faciale bilatérale ou unilatérale (hypoplasie malaire, élargissement de la pyramide nasale), malformations dentaires avec dysplasie de l’émail, doigts et orteils courts, atteinte oculaire avec choroïdose myopique. L’IRM réalisée chez 3 patients a montré une leucoencéphalopathie asymptomatique avec hypersignal de la substance blanche et dilatation des espaces de Virchow. Résultats Chez les deux premiers patients, le séquençage de l’exome en profondeur (144X à 228X) sur peau atteinte a identifié une même mutation en mosaïque p.Glu47Lys du gène RHOA , confirmée par séquençage ciblé (taux allélique : 33,5 % et 23,1 %), absente du sang. Cette mutation a également été identifiée par séquençage ciblé chez deux des autres patients ayant un phénotype similaire. Le cinquième patient était porteur d’une autre mutation postzygotique de RHOA , Pro71Ser, identifiée par séquençage de l’exome. La transfection de plasmides porteurs de ces mutations de RHOA dans des cellules NIH 3T3 en culture a montré une diminution de l’étalement cellulaire, de la formation de fibre de stress, et de la phosphorylation des effecteurs de RhoA , MYPT1 et MLC2, suggérant un effet dominant-négatif de ces mutations. Discussion Nous avons identifié une affection neuroectodermique jamais décrite à notre connaissance, causée par des mutations en mosaïque de RHOA , qui code la protéine RhoA , une petite GTPase de la superfamille Ras, impliquée dans le chimiotactisme, le guidage axonal, et le contrôle du cycle cellulaire. En plus des anomalies fonctionnelles mises en évidence, la forte conservation de la séquence de RHOA au cours de l’évolution est en faveur du caractère pathogène des mutations identifiées. Conclusion Cette dysplasie ectodermique en mosaïque liée à RHOA s’ajoute aux syndromes causés par des mutations létales, pour lesquelles la survie embryonnaire n’est possible que par mosaïcisme. Il s’agit d’une de premières caractérisations moléculaires d’un mosaïcisme pigmentaire, qui souligne l’importance de RHOA dans le développement cutané.
Published: 2017

8. Hedgehog Signaling Pathway Orchestrates Human Lung Branching Morphogenesis

Author: Randa Belgacemi, Soula Danopoulos, Gail Deutsch, Ian Glass, Valérian Dormoy, Saverio Bellusci, Denise Al Alam, Harbor UCLA Medical Center [Torrance, Ca.], Seattle Children's Research Institute [Seattle, WA, USA], University of Washington [Seattle], Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), German Center for Lung Research, and dormoy, valerian
Subjects: human lung, [SDV]Life Sciences [q-bio], Organogenesis, Hedgehog pathway, Catalysis, development, branching, Inorganic Chemistry, Mice, Morphogenesis, Animals, Humans, Hedgehog Proteins, Physical and Theoretical Chemistry, Child, Molecular Biology, Lung, Wnt Signaling Pathway, Spectroscopy, Organic Chemistry, General Medicine, Computer Science Applications, [SDV] Life Sciences [q-bio], Hernias, Diaphragmatic, Congenital, Signal Transduction
Abstract: International audience; The Hedgehog (HH) signaling pathway plays an essential role in mouse lung development. We hypothesize that the HH pathway is necessary for branching during human lung development and is impaired in pulmonary hypoplasia. Single-cell, bulk RNA-sequencing data, and human fetal lung tissues were analyzed to determine the spatiotemporal localization of HH pathway actors. Distal human lung segments were cultured in an air-liquid interface and treated with an SHH inhibitor (5E1) to determine the effect of HH inhibition on human lung branching, epithelial-mesenchymal markers, and associated signaling pathways in vitro. Our results showed an early and regulated expression of HH pathway components during human lung development. Inhibiting HH signaling caused a reduction in branching during development and dysregulated epithelial (SOX2, SOX9) and mesenchymal (ACTA2) progenitor markers. FGF and Wnt pathways were also disrupted upon HH inhibition. Finally, we demonstrated that HH signaling elements were downregulated in lung tissues of patients with a congenital diaphragmatic hernia (CDH). In this study, we show for the first time that HH signaling inhibition alters important genes and proteins required for proper branching of the human developing lung. Understanding the role of the HH pathway on human lung development could lead to the identification of novel therapeutic targets for childhood pulmonary diseases.
Published: 2022

9. C910 chemical compound inhibits the traffiking of several bacterial AB toxins with cross-protection against influenza virus

Author: Yu Wu, Nassim Mahtal, Eléa Paillares, Léa Swistak, Sara Sagadiev, Mridu Acharya, Caroline Demeret, Sylvie Van Der Werf, Florence Guivel-Benhassine, Olivier Schwartz, Serena Petracchini, Amel Mettouchi, Lucie Caramelle, Pierre Couvineau, Robert Thai, Peggy Barbe, Mathilde Keck, Priscille Brodin, Arnaud Machelart, Valentin Sencio, François Trottein, Martin Sachse, Gaëtan Chicanne, Bernard Payrastre, Florian Ville, Victor Kreis, Michel-Robert Popoff, Ludger Johannes, Jean-Christophe Cintrat, Julien Barbier, Daniel Gillet, Emmanuel Lemichez, TROTTEIN, François, Caractérisation d'un composé antitoxines bactériennes à large spectre - - ToxProtect_Larg_Spectr2019 - ANR-19-ASTR-0001 - ASTRID - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Research Laboratory on Drugs and Therapeutic Innovation - - LERMIT2010 - ANR-10-LABX-0033 - LABX - VALID, Toxines bactériennes - Bacterial Toxins, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Chimie Bio-Organique et de Marquage (SCBM), Seattle Children's Research Institute [Seattle, WA, USA], Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Virus et Immunité - Virus and immunity, Université Paris-Saclay, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Institut Pasteur [Paris] (IP), Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), This work was funded by the joint ministerial program of Research and Development against Chemical, Biological, Radiological, Nuclear and Explosive risks ( CBRNE ), grants from the Agence Nationale de la Recherche ( ANR-19-ASTR-0001 ), Labex IBEID ( ANR-10-LABX-62-IBEID ), and the French Alternative Energies and Atomic Energy Commission ( CEA ). N.M., E.P., L.C., and F.V. were supported by DGA-MRIS/AID scholarships with CEA or Pasteur. SIMoS and SCBM are members of the Laboratory of Excellence LERMIT and were supported by a grant from the Agence Nationale de la Recherche ( ANR-10-LABX-33 )., ANR-19-ASTR-0001,ToxProtect_Larg_Spectr,Caractérisation d'un composé antitoxines bactériennes à large spectre(2019), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-LABX-0033,LERMIT,Research Laboratory on Drugs and Therapeutic Innovation(2010), Virus et Immunité - Virus and immunity (CNRS-UMR3569), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV] Life Sciences [q-bio], Biological sciences, Multidisciplinary, [SDV]Life Sciences [q-bio], Microbiology
Abstract: International audience; The development of anti-infectives against a large range of AB-like toxin-producing bacteria includes the identification of compounds disrupting toxin transport through both the endolysosomal and retrograde pathways. Here, we performed a high-throughput screening of compounds blocking Rac1 proteasomal degradation triggered by the Cytotoxic Necrotizing Factor-1 (CNF1) toxin, which was followed by orthogonal screens against two toxins that hijack the endolysosomal (diphtheria toxin) or retrograde (Shiga-like toxin 1) pathways to intoxicate cells. This led to the identification of the molecule C910 that induces the enlargement of EEA1-positive early endosomes associated with sorting defects of CNF1 and Shiga toxins to their trafficking pathways. C910 protects cells against eight bacterial AB toxins and the CNF1-mediated pathogenic Escherichia coli invasion. Interestingly, C910 reduces influenza A H1N1 and SARS-CoV-2 viral infection in vitro. Moreover, parenteral administration of C910 to mice resulted in its accumulation in lung tissues and a reduction in lethal influenza infection.
Published: 2022

10. Genome instability drives epistatic adaptation in the human pathogen Leishmania

Author: Giovanni Bussotti, Laura Piel, Pascale Pescher, Malgorzata A. Domagalska, K. Shanmugha Rajan, Smadar Cohen-Chalamish, Tirza Doniger, Disha-Gajanan Hiregange, Peter J Myler, Ron Unger, Shulamit Michaeli, Gerald F. Späth, Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Parasitologie moléculaire et Signalisation / Molecular Parasitology and Signaling, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Institute of Tropical Medicine [Antwerp] (ITM), Bar-Ilan University [Israël], Weizmann Institute of Science [Rehovot, Israël], Seattle Structural Genomics Center for Infectious Disease (SSGCID), University of Washington [Seattle], Seattle Children's Research Institute [Seattle, WA, USA], This study was supported by a seeding grant from the Institut Pasteur International Department to the LeiSHield Consortium, the EU H2020 project LeiSHield-MATI-REP-778298-1, the Fondation pour la Recherche Médicale (Grant FDT201805005619), the Flemish Ministry of Science and Innovation (MADLEI, SOFI Grant 754204), and a grant from CAMPUS France and the Israeli Ministry of Science and Technology PHC MAIMONIDE 2018-2019-Projet 41131ZD., European Project: 778298,H2020,H2020-MSCA-RISE-2017,LeiSHield-MATI(2018), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris (UP), Ricard Andraos, Christel, and A multi-disciplinary international effort to identify clinical, molecular and social factors impacting cutaneous leishmaniasis - LeiSHield-MATI - - H20202018-04-01 - 2022-03-31 - 778298 - VALID
Subjects: Genome instability, 0303 health sciences, Experimental evolution, Multidisciplinary, [SDV]Life Sciences [q-bio], 030302 biochemistry & molecular biology, Robustness (evolution), Genomics, posttranscriptional regulation, Computational biology, fitness gain, Biology, epistatic interactions, Gene dosage, genome instability, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, evolutionary adaptation, Epistasis, Copy-number variation, Adaptation, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: How genome instability is harnessed for fitness gain despite its potential deleterious effects is largely elusive. An ideal system to address this important open question is provided by the protozoan pathogen Leishmania, which exploits frequent variations in chromosome and gene copy number to regulate expression levels. Using ecological genomics and experimental evolution approaches we provide first evidence that Leishmania adaptation relies on epistatic interactions between functionally associated gene copy number variations in pathways driving fitness gain in a given environment. We further uncover post-transcriptional regulation as a key mechanism that compensates for deleterious gene dosage effects and provides phenotypic robustness to genetically heterogenous parasite populations. Finally, we correlate dynamic variations in snoRNA gene dosage with changes in rRNA 2’-O-methylation and pseudouridylation, suggesting translational control is an additional layer of parasite adaptation. Leishmania genome instability is thus harnessed for fitness gain by genome-dependent variations in gene expression, and genome-independent, compensatory mechanisms. This allows for polyclonal adaptation and maintenance of genetic heterogeneity despite strong selective pressure. The epistatic adaptation described here needs to be considered in Leishmania epidemiology and biomarker discovery, and may be relevant to other fast evolving, eukaryotic cells that exploit genome instability for adaptation, such as fungal pathogens or cancer.One Sentence SummaryEpistatic interactions harness genome instability for Leishmania fitness gain.
Published: 2021

11. De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder

Author: Jonathan A. Bernstein, Leah J. Rowe, Kimberly Foss, Samin A. Sajan, Kun Xia, Juliane Hoyer, Anita E. Beck, Shayna Svihovec, Vincent Gatinois, Lance H. Rodan, Roksana Sasanfar, Christiane Zweier, Alban Ziegler, Sonal Mahida, Kristin G. Monaghan, Charlotte W. Ockeloen, André Reis, Milen Velinov, Janson White, Evan E. Eichler, Nasim Vasli, Jennifer Friedman, Constance Smith-Hicks, Gilles Morin, Rachel Westman, Sandra Yang, Joshua Scheck, Christian Thiel, John B. Vincent, Deborah A. Nickerson, Michelle E. Ernst, Jacqueline Harris, Natasha Zeid, Bernt Popp, Francesca Mattioli, Zehra Agha, Ellen van Binsbergen, Julian A. Martinez-Agosto, Karen W. Gripp, Gwenaël Le Guyader, Catherine Vincent-Delorme, Lori-Anne Schillaci, Jennefer N. Kohler, Kimberly A. Aldinger, Laurence J. Walsh, Jessica X. Chong, David Geneviève, Rami Abou Jamra, Amy Yang, Cigdem I. Akman, Sha Tang, Ricardo Harripaul, Rick Person, Marleen Simon, Hui Guo, Muhammad Ayub, Laura S. Farach, Patricia Blanchet, Austin Larson, Marie Vincent, Luis Rohena, Michael J. Bamshad, Raheel Qamar, Gregory M. Enns, Joshua Rotenberg, Katelyn Payne, William J. Sunderland, Anne C.-H. Tsai, Annika M. Dries, Michèle Mathieu-Dramard, Dominique Bonneau, Ghayda M. Mirzaa, Bénédicte Gérard, Elise Schaefer, Amélie Piton, Patricia G Wheeler, Division of Medical Genetics [Seattle], University of Washington [Seattle], Détoxication et réparation tissulaire, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, Central South University [Changsha], Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Center for Integrative Brain Research, Ambry Genetics [Aliso Viejo, CA, USA], China Agricultural University (CAU), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Kennedy Krieger Institute [Baltimore], Institute of Human Genetics [Erlangen, Allemagne], Universität Leipzig, Yale University [New Haven], Oregon Health and Science University [Portland] (OHSU), McGovern Medical School [Houston, Texas], Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Indiana University [South Bend], The University of Texas at San Antonio (UTSA), New York State Psychiatric Institute, Columbia University [New York], Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], CHU Strasbourg, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University Medical Center [Utrecht], Stanford University School of Medicine [CA, USA], Memorial Hermann Heart and Vascular Institute [Houston, TX, USA], University of Central Florida [Orlando] (UCF), Department of Pediatrics [Univ California San Diego] (UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), University of Colorado Anschutz [Aurora], Department of Chemistry and Biochemistry [Bern], University of Bern, Columbia University Irving Medical Center (CUIMC), Signal Processing Lab [Boise - Idaho], Boise State University, University Hospitals Case Medical Center (CLEVELAND - UHCMC), University Hospitals Case Medical Center, Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Psychology [University North Carolina Wilmington], University of North Carolina [Wilmington] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), 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), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'hématologie et immunologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Institut d'histoire du temps présent (IHTP), Centre National de la Recherche Scientifique (CNRS), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Queen's University [Kingston, Canada], Department of Molecular Genetics [Toronto], University of Toronto, GeneDx [Gaithersburg, MD, USA], Department of Genome Sciences [Seattle] (GS), Department of Pediatrics [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford School of Medicine [Stanford], Stanford University, University of California (UC), COMSATS Institute of Information Technology [Islamabad] (CIIT), Boston Children's Hospital, University of California [Los Angeles] (UCLA), Radboud University Medical Center [Nijmegen], Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Psychiatry, Seattle University [Seattle], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Leipzig [Leipzig], Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Pediatrics [san Diego], UC San Diego School of Medicine, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and University of California
Subjects: 0301 basic medicine, Proband, Male, Adolescent, Autism Spectrum Disorder, autism spectrum disorders, Nerve Tissue Proteins, Neuroimaging, 030105 genetics & heredity, Biology, Article, 03 medical and health sciences, Neurodevelopmental disorder, ZNF292, Intellectual disability, mental disorders, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, Child, Genetics (clinical), Exome sequencing, Genetics, Zinc finger, next generation sequencing, Genetic heterogeneity, High-Throughput Nucleotide Sequencing, medicine.disease, Phenotype, 3. Good health, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, intellectual disability, Neurodevelopmental Disorders, Child, Preschool, next-generation sequencing, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Carrier Proteins, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract: Contains fulltext : 218267.pdf (Publisher’s version ) (Closed access) PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292). METHODS: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships. RESULTS: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment. CONCLUSION: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.
Published: 2019

12. DLG4-related synaptopathy: a new rare brain disorder

Author: Edgard Verdura, Alex MacKenzie, Rolph Pfundt, Tobias B. Haack, Ange Line Bruel, Paulino Gómez-Puertas, Anna C.E. Hurst, Bert B.A. de Vries, Stella A. de Man, Maria Johansson Soller, Bregje W.M. van Bon, Elisabeth Sarrazin, Agustí Rodríguez-Palmero, Stephan Waldmüller, Melanie O’Leary, Anne Sophie Denommé-Pichon, Bitten Schönewolf-Greulich, Joseph T. Shieh, V. A. Bjerregaard, Vahid Bahrambeigi, Malin Kvarnung, Agatha Schlüter, Anne Marie Bisgaard, Ingrid M.B.H. van de Laar, Elisa Giorgio, Lars Feuk, Mieke M. van Haelst, Thomas D. Challman, Ineke van de Burgt, Sulagna Kushary, Simone F. Reiter, David B. Everman, Zeynep Tümer, Giorgia Mandrile, Conny M. A. van Ravenswaaij-Arts, Charles Shaw-Smith, Juliane Hoyer, Chad R. Haldeman-Englert, Lotte Kleinendorst, Bryce A. Mendelsohn, Anna Lindstrand, Christine Coubes, Gea Beunders, Sixto García-Miñaur, Antonio Vitobello, Melissa Maria Boerrigter, Alysia Kern Lovgren, Anya Revah-Politi, Carlos E. Prada, Bertrand Isidor, Elena Repnikova, Stephanie Spranger, Esmée van Drie, Frédéric Tran Mau-Them, Zohra Shad, Ben Pode-Shakked, Aurora Pujol, Christiane Zweier, Bjørn Ivar Haukanes, David Gómez-Andrés, Kathleen A. Leppig, Marta Pacio-Míguez, Motti Shohat, Yuval Landau, Benjamin Cogné, Frances Elmslie, Kimberly A. Aldinger, Anita Rauch, Juliann M. Savatt, Nicolas Gruchy, Sharon Whiting, William B. Dobyns, Thomas J. Dye, Sebastien Moutton, Heidi Thiese, Setareh Moghadasi, Iñigo Marcos-Alcalde, Jenny Morton, Sumit Parikh, María Palomares-Bralo, Stéphanie Arpin, Tracy S. Gertler, Meredith J. Ross, Bernt Popp, Amelie J. Müller, Claudia A. L. Ruivenkamp, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), CIBER de Enfermedades Raras (CIBERER), Hospital Universitario Germans Trias I Pujol, Vall d'Hebron University Hospital [Barcelona], Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Department of Molecular and Human Genetics (Baylor College of Medicine), Baylor College of Medecine, Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Clinical Genetics, Human Genetics, Graduate School, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ARD - Amsterdam Reproduction and Development, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
Subjects: 0301 basic medicine, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], 030105 genetics & heredity, Biology, 03 medical and health sciences, Intellectual Disability, Intellectual disability, medicine, Missense mutation, Humans, Global developmental delay, Exome, Genetics (clinical), Genetics, Brain Diseases, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Brain, medicine.disease, 030104 developmental biology, Phenotype, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Autism spectrum disorder, Neurodevelopmental Disorders, Synaptopathy, DLG4, Postsynaptic density, Disks Large Homolog 4 Protein
Abstract: Contains fulltext : 245031.pdf (Publisher’s version ) (Closed access) PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.
Published: 2021

13. CYP3A-mediated apoptosis of dauricine in cultured human bronchial epithelial cells and in lungs of CD-1 mice

Author: Zheng, Jiang [Center for Developmental Therapeutics, Seattle Children's Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington, Seattle, WA 98101 (United States)]
Published: 2012
Full Text: View/download PDF

14. Author Correction: Postzygotic inactivating mutations of RHOA cause a mosaic neuroectodermal syndrome [Correction to: Nature Genetics https://doi.org/10.1038/s41588-019-0498-4, published online 30 September 2019]

Author: Vabres, Pierre, Sorlin, Arthur, Kholmanskikh, Stanislav S., Demeer, Bénédicte, St Onge, Judith, Duffourd, Yannis, Kuentz, Paul, Courcet, Jean-Benoît, Carmignac, Virginie, Garret, Philippine, Bessis, Didier, Boute, Odile, Bron, Alain, Captier, Guillaume, Carmi, Esther, Devauchelle, Bernard, Genevieve, David, Gondry Jouet, Catherine, Guibaud, Laurent, Lafon, Arnaud, Mathieu Dramard, Michèle, Thévenon, Julien, Dobyns, William B., Bernard, Geneviève, Polubothu, Satyamaanasa, Faravelli, Francesca, Kinsler, Veronica A., Thauvin, Christel, Faivre, Laurence, Ross, M. Elizabeth, Rivière, Jean-Baptiste, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Weill Cornell Medicine, CHU Amiens-Picardie, McGill University = Université McGill [Montréal, Canada], Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Centre Hospitalier Universitaire de Lille (CHU de Lille), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Bourgogne Franche-Comté [COMUE] (UBFC), Dermatology Office, Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Seattle Children’s Research Institute, Montreal Children’s Hospital, University College of London [London] (UCL), and ProdInra, Migration
Subjects: [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], [SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT], [SDV.BDD] Life Sciences [q-bio]/Development Biology, [SDV.BDD]Life Sciences [q-bio]/Development Biology
Abstract: Indexation en cours. In the version of this article initially published, support from the Wellcome Trust and NIHR to author Veronica A. Kinsler was not included in the Acknowledgements. The error has been corrected in the HTML and PDF versions of the article.; International audience; An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2020

15. De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature

Author: Nambot, Sophie, Faivre, Laurence, Mirzaa, Ghayda, Thevenon, Julien, Bruel, Ange-Line, Mosca-Boidron, Anne-Laure, Masurel-Paulet, Alice, Goldenberg, Alice, Le Meur, Nathalie, Charollais, Aude, Mignot, Cyril, Petit, Florence, Rossi, Massimiliano, Metreau, Julia, Layet, Valérie, Amram, Daniel, Boute-Bénéjean, Odile, Bhoj, Elizabeth, Cousin, Margot, Kruisselbrink, Teresa, Lanpher, Brendan, Klee, Eric, Fiala, Elise, Grange, Dorothy, Meschino, Wendy, Hiatt, Susan, Cooper, Gregory, Olivié, Hilde, Smith, Wendy, Dumas, Meghan, Lehman, Anna, Inglese, Cara, Nizon, Mathilde, Guerrini, Renzo, Vetro, Annalisa, Kaplan, Eitan, Miramar, Dolores, van Gils, Julien, Fergelot, Patricia, Bodamer, Olaf, Herkert, Johanna, Pajusalu, Sander, Õunap, Katrin, Filiano, James, Smol, Thomas, Piton, Amélie, Gérard, Bénédicte, Chantot-Bastaraud, Sandra, Bienvenu, Thierry, Li, Dong, Juusola, Jane, Devriendt, Koen, Bilan, Frederic, Poé, Charlotte, Chevarin, Martin, Jouan, Thibaud, Tisserant, Emilie, Rivière, Jean-Baptiste, Tran Mau-Them, Frédéric, Philippe, Christophe, Duffourd, Yannis, Dobyns, William, Hevner, Robert, Thauvin-Robinet, Christel, Couvet, Sandrine, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD (CHU de Dijon), Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, Department of Pediatrics [Seattle], University of Washington [Seattle], Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Service de pédiatrie médicale et médecine de l'adolescent [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Service de Génétique [CHU Lyon] (Centre de pathologie de l'Est), Hospices civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Genetics of Neurodevelopment (GENDEV), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Service de Neurologie Pédiatrique [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Département de génétique (groupe hospitalier le Havre), Groupe Hospitalier du Havre, Centre Hospitalier Intercommunal de Créteil (CHIC), Department of Pediatrics [Philadelphia, PA, USA] (Division of Genetics), Children’s Hospital of Philadelphia (CHOP ), The Center for Applied Genomics [Philadelphia, PA, USA], Mayo Clinic [Rochester], Department of Pediatrics [Saint Louis, MO, USA] (Division of Genetics and Genomic Medicine), Washington University in Saint Louis (WUSTL), Department of Genetics [Saint-Louis], HudsonAlpha Institute for Biotechnology [Huntsville, AL], University Hospitals Leuven [Leuven], Maine Medical Center, University of British Columbia [Vancouver], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Meyer Children's Hospital [Florence, Italie], Università degli Studi di Firenze = University of Florence (UniFI), CHU Bordeaux [Bordeaux], Department of Genetics [Boston], Harvard Medical School [Boston] (HMS), University Medical Center Groningen [Groningen] (UMCG), University of Tartu, Dartmouth Hitchcock Medical Center [Lebanon, NH, USA] (DHMC), Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], UF de Génétique chromosomique [CHU Trousseau], Service de Génétique et Biologie Moléculaires [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), GeneDx [Gaithersburg, MD, USA], Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)
Subjects: Proband, Candidate gene, INTELLECTUAL DISABILITY, MESH: Hippocampus, [SDV]Life Sciences [q-bio], MESH: Cognition, MESH: Neocortex, MESH: Child, Intellectual disability, MESH: Craniofacial Abnormalities, MESH: Animals, MESH: Syndrome, Genetics (clinical), Genetics, PROGENITORS, biology, Phenotype, NEOCORTEX, [SDV] Life Sciences [q-bio], EXPRESSION, GENES, MESH: Mutation, MESH: T-Box Domain Proteins, MESH: Autistic Disorder, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Phenotype, Article, REGION, MESH: Intellectual Disability, NEUROGENESIS, Dysgenesis, FEZF2, medicine, MESH: Mice, MESH: Adolescent, MESH: Humans, MUTATIONS, business.industry, MESH: Child, Preschool, MESH: Adult, medicine.disease, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, Autism, TBR1, business, Neurocognitive, MESH: Female
Abstract: International audience; TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands.
Published: 2020

16. NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

Author: Sonal Mahida, Elliott H. Sherr, Elodie Lacaze, William B. Dobyns, Kosuke Izumi, Hilde Peeters, Marielle Alders, Catherine Nowak, Dawn L. Earl, Richard M. Gronostajski, Ryan J. Dean, Megan T. Cho, Anouck Schneider, Siren Berland, Patricia Blanchet, Laurence Faivre, Martin Zenker, Ina Schanze, Caitlin J. Bridges, Daniela T. Pilz, Sangamitra Boppudi, Ilse Wieland, Jens Bunt, Avni Santani, Jessica Douglas, Elaine H. Zackai, Muriel Holder-Espinasse, Linda J. Richards, Jean Baptiste Rivière, Tania Attié-Bitach, Timothy J. Edwards, Vincent Gatinois, Jacques Puechberty, Jonathan W. C. Lim, Ghayda Mirzaa, Sian Morgan, Phillis Lakeman, Steven Boogert, Samuel Huth, Marion Gérard, Denny Schanze, Florence Petit, Xiaonan Zhao, Eyal Reinstein, David Geneviève, Bronwyn Kerr, Dian Donnai, Constance Smith-Hicks, Brieana Fregeau, Amsterdam Reproduction & Development (AR&D), ACS - Pulmonary hypertension & thrombosis, Human Genetics, Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), Queensland Brain Institute, University of Queensland [Brisbane], University of Amsterdam [Amsterdam] (UvA), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Embryology and genetics of human malformation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Haukeland University Hospital, University of Bergen (UiB), GeneDx [Gaithersburg, MD, USA], University of Washington [Seattle], Seattle Children’s Hospital, University of Manchester [Manchester], Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD (CHU de Dijon), University of California [San Francisco] (UC San Francisco), University of California (UC), Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), 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), CHU Lille, Children’s Hospital of Philadelphia (CHOP ), Département de génétique (groupe hospitalier le Havre), Groupe Hospitalier du Havre, Kennedy Krieger Institute [Baltimore], University Hospital of Wales (UHW), University Hospitals Leuven [Leuven], University of Glasgow, Sackler Faculty of Medicine, Tel Aviv University (TAU), Perelman School of Medicine, University of Pennsylvania, This work was supported by grants from the National Healthand Medical Research Council Australia (GNT1100443 to L.J.R.), the French Ministry of Health (PHRC national 2008/2008-A00515-50), Regional Council of Burgundy/Dijon University hospital (PARI 2012), The Genesis Foundation for Children, the US National Institutes of Health under NINDS grants(1R01NS092772 and 234567890 to W.B.D., 1R01NS058721 toW.B.D. and E.H.S., and K08NS092898 to G.M.M.), and Jordan’s Guardian Angels (G.M.M.). J.W.C.L. was supported by an International Postgraduate Research Scholarship and UQ Centennial Scholarship. R.M.G. was supported by NYSTEM grants (C026714,C026429, and C030133). R.J.D. was supported by Brain Injured Children’s Aftercare Recovery Endeavours (BICARE) Fellowship.L.J.R. was supported by an NHMRC Principal Research Fellowship(GNT1005751). M.Z. was supported by a grant from the GermanMinistry of Education and Research (BMBF) (GeNeRARe01GM1519A). We acknowledge the Linkage Infrastructure, Equipment and Facilities (LIEF) grant (LE100100074) awarded to the Queensland Brain Institute for the Slide Scanner and the facilities of the National Imaging Facility (NIF) at the Centre for Advanced Imaging, University of Queensland, used in the animal experiments., European Project: 270259,EC:FP7:ICT,FP7-ICT-2009-6,TBICARE(2011), Institute of Human Genetics (University Hospital Magdeburg), University Hospital of the Otto von Guericke University of Magdeburg, Department of Clinical Genetics, Academic Medical Centre, Amsterdam, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Bergen (UIB), Seattle Children's Research Institute, Department of Neurology (University of California : San Francisco), University of California [San Francisco] (UCSF), University of California-University of California, Department of Medical Genetics, HMNC Brain Health, Seattle Children’s Hospital [Seattle, WA, USA], Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Université de Lorraine (UL), Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Pediatrics (Perelman School of Medicine), University of Pennsylvania [Philadelphia], Regional Genetic Service, St Mary's Hospital, Manchester, Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Department of Pediatrics [Seattle, WA, USA] (Division of Genetic Medicine), University of Washington [Seattle]-Seattle Children’s Hospital [Seattle, WA, USA], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales, Center for Human Genetics, University Hospitals Leuven, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille 2 - Faculté de Médecine -Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Medical Genetics Institute, Meir Medical Center, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA], University of Pennsylvania [Philadelphia]-Perelman School of Medicine, Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, School of Computer Science and Technology, Northwestern Polytechnical University [Xi'an] (NPU), Department of Biochemistry and Developmental Genomics Group, University at Buffalo [SUNY] (SUNY Buffalo), State University of New York (SUNY)-State University of New York (SUNY)-Center of Excellence in Bioinformatics and Life Sciences, Institute of Human Genetics, University Hospital Magdeburg, université de Bourgogne, LNC, Evidence based Diagnostic and Treatment Planning Solution for Traumatic Brain Injuries - TBICARE - - EC:FP7:ICT2011-02-01 - 2014-07-31 - 270259 - VALID, Otto-von-Guericke University [Magdeburg] (OVGU), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of California, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Hospital of Wales [Cardiff, UK], and Tel Aviv University [Tel Aviv]
Subjects: Male, 0301 basic medicine, chromosome 9p23, Medical and Health Sciences, Corpus Callosum, Cohort Studies, Mice, 2.1 Biological and endogenous factors, Megalencephaly, Aetiology, Child, Agenesis of the corpus callosum, Genetics (clinical), Pediatric, Genetics & Heredity, Cerebral Cortex, Mice, Knockout, Genetics, Single Nucleotide, nuclear factor I, Biological Sciences, NFIB, NFIX, developmental delay, Mental Health, Codon, Nonsense, NFIA, intellectual disability, Child, Preschool, chromosome 9p22.3, Neurological, Speech delay, Female, medicine.symptom, Haploinsufficiency, Adult, Adolescent, Knockout, Intellectual and Developmental Disabilities (IDD), [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, macrocephaly, Polymorphism, Single Nucleotide, Article, Young Adult, 03 medical and health sciences, Rare Diseases, Behavioral and Social Science, medicine, megalencephaly, Animals, Humans, Polymorphism, Codon, Preschool, Neurosciences, Macrocephaly, medicine.disease, Brain Disorders, haploinsufficiency, NFI Transcription Factors, 030104 developmental biology, Nonsense, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, agenesis of the corpus callosum
Abstract: The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:103 issue:5 pages:752-768 ispartof: location:United States status: published
Published: 2018

17. Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis

Author: Baragaña, Beatriz, Forte, Barbara, Choi, Ryan, Nakazawa Hewitt, Stephen, Bueren-Calabuig, Juan A., Pisco, João Pedro, Peet, Caroline, Dranow, David M., Robinson, David A., Jansen, Chimed, Norcross, Neil R., Vinayak, Sumiti, Anderson, Mark, Brooks, Carrie F., Cooper, Caitlin A., Damerow, Sebastian, Delves, Michael, Dowers, Karen, Duffy, James, Edwards, Thomas E., Hallyburton, Irene, Horst, Benjamin G., Hulverson, Matthew A., Ferguson, Liam, Jiménez-Díaz, María Belén, Jumani, Rajiv S., Lorimer, Donald D., Love, Melissa S., Maher, Steven, Matthews, Holly, McNamara, Case W., Miller, Peter, O’Neill, Sandra, Ojo, Kayode K., Osuna-Cabello, Maria, Pinto, Erika, Post, John, Riley, Jennifer, Rottmann, Matthias, Sanz, Laura M., Scullion, Paul, Sharma, Arvind, Shepherd, Sharon M., Shishikura, Yoko, Simeons, Frederick R. C., Stebbins, Erin E., Stojanovski, Laste, Straschil, Ursula, Tamaki, Fabio K., Tamjar, Jevgenia, Torrie, Leah S., Vantaux, Amélie, Witkowski, Benoît, Wittlin, Sergio, Yogavel, Manickam, Zuccotto, Fabio, Angulo-Barturen, Iñigo, Sinden, Robert, Baum, Jake, Gamo, Francisco-Javier, Mäser, Pascal, Kyle, Dennis E., Winzeler, Elizabeth A., Myler, Peter J., Wyatt, Paul G., Floyd, David, Matthews, David, Sharma, Amit, Striepen, Boris, Huston, Christopher D., Gray, David W., Fairlamb, Alan H., Pisliakov, Andrei V., Walpole, Chris, Read, Kevin D., Van Voorhis, Wesley C., Gilbert, Ian H., University of Dundee, Seattle Structural Genomics Center for Infectious Disease (SSGCID), University of Washington [Seattle], Beryllium Discovery Corp. [Bainbridge Island, WA], University of Georgia [USA], Imperial College London, Medicines for Malaria Venture [Geneva] (MMV), The Art of Discovery [Bizkaia, Spain] (TAD), University of Vermont [Burlington], Scripps Research Institute, Swiss Tropical and Public Health Institute [Basel], University of Basel (Unibas), GlaxoSmithKline (GSK), International Centre for Genetic Engineering and Biotechnology [New Delhi] (ICGEB), Malaria Molecular Epidemiology, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), University of California [San Diego] (UC San Diego), University of California, Seattle Children's Research Institute [Seattle, WA, USA], University of Toronto, University of Pennsylvania [Philadelphia], McGill University = Université McGill [Montréal, Canada], This work was supported by the Bill and Melinda Gates Foundation through Grant OPP1032548 to the Structure-Guided Drug Discovery Coalition and OPP1134302 (to B.S.). This work was also supported in part from federal funds, from the NIH/National Institute of Allergy and Infectious Diseases Grant R21AI123690 (to K.K.O.) and Contracts HHSN272201200025C and HHSN272201700059C (to P.J.M.), Medicines for Malaria Venture (through access to assays to I.H.G. and through RD/08/2800 to J.B.), Wellcome Trust for support of the X-ray Crystallography Facility 094090, IT support Grant 105021 (to I.H.G.), and Institutional Strategic Support Fund 204816 (to A.V.P.), all at the University of Dundee and for Investigator Award 100993 (to J.B.)., We thank the European Synchrotron Radiation Facility for beamtime, highlighting the staff of beamlines BM14 and ID29, Diamond Light Source for beamtime (proposal mx10071), the staff of beamline I24 for assistance with crystal testing and data collection, the entire Seattle Structural Genomics Center for Infectious Disease team, the Division of Biological Chemistry and Drug Discovery Protein Production Team, GlaxoSmithKline for the Tres Campos Antimalarial screening set, the Scottish Blood Transfusion Centre (Ninewells Hospital, Dundee) for providing human erythrocytes, Christoph Fischli and Sibylle Sax at the SwissTPH for technical assistance with the SCID mouse model, and and Anja Schäfer for technical assistance with the in vitro antimalarial activity testing. The Art of Discovery thanks Dr. Cristina Eguizabal and the Basque Center of Transfusion and Human Tissues (Galdakao, Spain) and the Bank of Blood and Tissues (Barcelona, Spain) for providing human blood. The University of California, San Diego thanks Jenya Antonova-Koch for help.
Subjects: Lysine-tRNA Ligase, tRNA synthetase, Plasmodium falciparum, Protozoan Proteins, malaria, Mice, SCID, Microbiology, parasitic diseases, Animals, Humans, MESH: Animals, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Enzyme Inhibitors, Malaria, Falciparum, MESH: Mice, SCID, MESH: Protozoan Proteins, MESH: Plasmodium falciparum, Cryptosporidium parvum, MESH: Humans, cryptosporidiosis, MESH: Lysine-tRNA Ligase, MESH: Malaria, Falciparum, MESH: Cryptosporidiosis, Biological Sciences, Chemistry, Disease Models, Animal, MESH: Enzyme Inhibitors, Physical Sciences, MESH: Cryptosporidium parvum, MESH: Disease Models, Animal
Abstract: Significance Malaria and cryptosporidiosis are major burdens to both global health and economic development in many countries. Malaria caused >400,000 deaths in 2017, and cryptosporidiosis is estimated to cause >200,000 deaths a year. The spread of drug resistance is a growing concern for malaria treatment, and there is no effective treatment for malnourished or immunocompromised children infected with Cryptosporidium. New treatments with novel mechanisms of action are needed for both diseases. We present a selective inhibitor of both Plasmodium and Cryptosporidium lysyl-tRNA synthetase capable of clearing parasites from mouse models of malaria and cryptosporidiosis infection. This provides very strong validation of lysyl-tRNA synthetase as a drug target in these organisms and a lead for further drug discovery., Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies. Target deconvolution in P. falciparum has shown that cladosporin inhibits lysyl-tRNA synthetase (PfKRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both PfKRS1 and C. parvum KRS (CpKRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED90 = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between PfKRS1 and CpKRS. This series of compounds inhibit CpKRS and C. parvum and Cryptosporidium hominis in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for PfKRS1 and CpKRS vs. (human) HsKRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.
Published: 2019

18. Author Correction: Postzygotic inactivating mutations of RHOA cause a mosaic neuroectodermal syndrome

Author: V. Carmignac, Yannis Duffourd, Geneviève Bernard, Bénédicte Demeer, Didier Bessis, Christel Thauvin, Bernard Devauchelle, Odile Boute, Philippine Garret, Arthur Sorlin, Esther Carmi, Julien Thevenon, Veronica A. Kinsler, Arnaud Lafon, Alain Bron, S.S. Kholmanskikh, Catherine Gondry-Jouet, William B. Dobyns, Guillaume Captier, Paul Kuentz, Pierre Vabres, Jean Benoît Courcet, Laurent Guibaud, David Geneviève, Jean Baptiste Rivière, Satyamaanasa Polubothu, Francesca Faravelli, Judith St-Onge, Laurence Faivre, M. Elizabeth Ross, Michèle Mathieu-Dramard, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC), Weill Cornell Medicine, CHU Amiens-Picardie, MCGill University Health Centre, Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Centre Hospitalier Universitaire de Lille (CHU de Lille), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Dermatology Office, Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Seattle Children’s Research Institute, Montreal Children’s Hospital, University College of London [London] (UCL), McGill University = Université McGill [Montréal, Canada], UMR 1231, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), MCGill University, ProdInra, Archive Ouverte, and Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement
Subjects: Genetics, 0303 health sciences, RHOA, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Mosaic (geodemography), 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, biology.protein, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030304 developmental biology
Abstract: Published Erratum: Correction to: Nature Genetics 51: 1438–1441 https://doi.org/10.1038/s41588-019-0498-4, published online 30 September 2019.In the version of this article initially published, authors Bénédicte Demeer and Bernard Devauchelle were missing the affiliation EA CHIMERE–7516, Université Picardie Jules Verne, Amiens, France. The error has been corrected in the HTML and PDF versions of the article.; An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2019

19. Rubella Virus-Associated Cutaneous Granulomatous Disease : a Unique Complication in Immune-Deficient Patients, Not Limited to DNA Repair Disorders

Author: Philippe Pérot, Hans D. Ochs, Bénédicte Neven, David Buchbinder, Jasjit Singh, Christine Bodemer, E.V. Deripapa, Louise E. Vaz, Despina Moshous, Fabian Hauck, Kathleen E. Sullivan, Christoph Klein, Anna Shcherbina, Michael H. Albert, Shahrzad Bakhtiar, Felipe Suarez, Anita Rack, Diane J. Nugent, Francisco A. Bonilla, Marc Eloit, Alfons Krol, Ludmila Perelygina, Mikko Seppänen, Children's Hospital, Clinicum, HUS Children and Adolescents, University of California [Irvine] (UC Irvine), University of California (UC), Children's Hospital of Orange County, Dr von Hauner Children's Hospital [Munich, Germany], Ludwig-Maximilians-Universität München (LMU), Frankfurt University Hospital, Dmitry Rogachev Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Children’s Hospital of Philadelphia (CHOP ), Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, Biologie des Infections - Biology of Infection, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche et Innovation Technologique (CITECH), Institut Pasteur [Paris] (IP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Boston Children's Hospital, Oregon Health & Sciences University, Oregon Health and Science University [Portland] (OHSU), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Seattle Children's Research Institute [Seattle, WA, USA], University of Washington [Seattle], We thank the patients and their families for participating in our research studies. We would also like to acknowledge the support of the U.S. Centers for Disease Control and Prevention in Atlanta, GA. Patient blood samples and biopsy material were obtained after provision of informed consent., Pérot, Philippe, University of California [Irvine] (UCI), University of California, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris], and University of Helsinki
Subjects: Male, 0301 basic medicine, chronic rubella infection resulting in cutaneous granuloma formation, DNA Repair, MESH: Granuloma, MESH: X-Linked Combined Immunodeficiency Diseases, X-Linked Combined Immunodeficiency Diseases, medicine.disease_cause, MESH: Ataxia Telangiectasia, MESH: Hirschsprung Disease, Hypogammaglobulinemia, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, Immunology and Allergy, combined immunodeficiency, Child, MESH: Nijmegen Breakage Syndrome, Immunodeficiency, Skin, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: DNA Repair, Granuloma, Hematopoietic Stem Cell Transplantation, MESH: Rubella, Rubella virus, DNA ligase 4 deficiency, 3. Good health, Child, Preschool, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, ataxia telangiectasia, MESH: Hair, medicine.medical_specialty, Adolescent, MESH: Immunologic Deficiency Syndromes, Nijmegen breakage syndrome, Primary Immunodeficiency Diseases, Immunology, MESH: Skin Diseases, Osteochondrodysplasias, Skin Diseases, Rubella, Article, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Skin, medicine, Humans, Hirschsprung Disease, Artemis deficiency, MESH: Hematopoietic Stem Cell Transplantation, MESH: Adolescent, Myelokathexis, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Humans, business.industry, MUTATIONS, MESH: Child, Preschool, Immunologic Deficiency Syndromes, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, MESH: Osteochondrodysplasias, medicine.disease, Dermatology, MESH: Male, Transplantation, MESH: Rubella virus, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, Primary immunodeficiency, MESH: Primary Immunodeficiency Diseases, business, MESH: Female, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Hair, 030215 immunology
Abstract: International audience; The association of immunodeficiency-related vaccine-derived rubella virus (iVDRV) with cutaneous and visceral granulomatous disease has been reported in patients with primary immunodeficiency disorders (PIDs). The majority of these PID patients with rubella-positive granulomas had DNA repair disorders. To support this line of inquiry, we provide additional descriptive data on seven previously reported patients with Nijmegen breakage syndrome (NBS) (n = 3) and ataxia telangiectasia (AT) (n = 4) as well as eight previously unreported patients with iVDRV-induced cutaneous granulomas and DNA repair disorders including NBS (n = 1), AT (n = 5), DNA ligase 4 deficiency (n = 1), and Artemis deficiency (n = 1). We also provide descriptive data on several previously unreported PID patients with iVDRV-induced cutaneous granulomas including cartilage hair hypoplasia (n = 1), warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome (n = 1), MHC class II deficiency (n = 1), Coronin-1A deficiency (n = 1), X-linked severe combined immunodeficiency (X-SCID) (n = 1), and combined immunodeficiency without a molecular diagnosis (n = 1). At the time of this report, the median age of the patients with skin granulomas and DNA repair disorders was 9 years (range 3-18). Cutaneous granulomas have been documented in all, while visceral granulomas were observed in six cases (40%). All patients had received rubella virus vaccine. The median duration of time elapsed from vaccination to the development of cutaneous granulomas was 48 months (range 2-152). Hematopoietic cell transplantation was reported to result in scarring resolution of cutaneous granulomas in two patients with NBS, one patient with AT, one patient with Artemis deficiency, one patient with DNA Ligase 4 deficiency, one patient with MHC class II deficiency, and one patient with combined immunodeficiency without a known molecular etiology. Of the previously reported and unreported cases, the majority share the diagnosis of a DNA repair disorder. Analysis of additional patients with this complication may clarify determinants of rubella pathogenesis, identify specific immune defects resulting in chronic infection, and may lead to defect-specific therapies.
Published: 2019

20. Does 3D Phenotyping Yield Substantial Insights in the Genetics of the Mouse Mandible Shape?

Author: Nicolas Navarro, A. Murat Maga, Biogéosciences [Dijon] ( BGS ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), École pratique des hautes études ( EPHE ), Division of Craniofacial Medicine, University of Washington [Seattle], Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Work supported by a National Institutes of Health/National Institute of Dental and Craniofacial Research Pathways to Independence award (5K99DE021417-02), and Conseil Régional de Bourgogne (CRB) funding (CRB PARI Agrale 5 Faber 2014-9201AAO047S01518), Biogéosciences [UMR 6282] [Dijon] (BGS), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)
Subjects: Models, Anatomic, 0301 basic medicine, Quantitative Trait Loci, Mandible, QH426-470, Investigations, Biology, Quantitative trait locus, [ SDV.BDD.MOR ] Life Sciences [q-bio]/Development Biology/Morphogenesis, Mice, 03 medical and health sciences, Imaging, Three-Dimensional, Genetics, Animals, Mus musculus, Molecular Biology, Genetic Association Studies, Genetics (clinical), Morphometrics, Landmark, business.industry, Digital imaging, Chromosome Mapping, [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis, [ SDV.GEN.GA ] Life Sciences [q-bio]/Genetics/Animal genetics, Pattern recognition, multivariate QTL mapping, Anatomy, Genetic architecture, 3D geometric morphometrics, Anatomical landmark, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, mandible shape, Phenotype, 030104 developmental biology, Artificial intelligence, business, Algorithms, Bone surface
Abstract: We describe the application of high-resolution 3D microcomputed tomography, together with 3D landmarks and geometric morphometrics, to validate and further improve previous quantitative genetic studies that reported QTL responsible for variation in the mandible shape of laboratory mice using a new backcross between C57BL/6J and A/J inbred strains. Despite the increasing availability of 3D imaging techniques, artificial flattening of the mandible by 2D imaging techniques seems at first an acceptable compromise for large-scale phenotyping protocols, thanks to an abundance of low-cost digital imaging systems such as microscopes or digital cameras. We evaluated the gain of information from considering explicitly this additional third dimension, and also from capturing variation on the bone surface where no precise anatomical landmark can be marked. Multivariate QTL mapping conducted with different landmark configurations (2D vs. 3D; manual vs. semilandmarks) broadly agreed with the findings of previous studies. Significantly more QTL (23) were identified and more precisely mapped when the mandible shape was captured with a large set of semilandmarks coupled with manual landmarks. It appears that finer phenotypic characterization of the mandibular shape with 3D landmarks, along with higher density genotyping, yields better insights into the genetic architecture of mandibular development. Most of the main variation is, nonetheless, preferentially embedded in the natural 2D plane of the hemi-mandible, reinforcing the results of earlier influential investigations.
Published: 2016

21. Homozygous TAF8 mutation in a patient with intellectual disability results in undetectable TAF8 protein, but preserved RNA polymerase II transcription

Author: Didier Devys, Matthieu Stierle, Mathew P. Dixon, Farrah El-Saafin, Laszlo Tora, Luc Negroni, Imre Berger, Jean Marie Garnier, William B. Dobyns, Natalie L. Downer, Anne K. Voss, Tim Thomas, Isabelle Kolb-Cheynel, Cynthia J. Curry, Tao Ye, 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 génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), European Molecular Biology Laboratory [Grenoble] (EMBL), and Seattle Children's Research Institute
Subjects: 0301 basic medicine, Transcription, Genetic, [SDV]Life Sciences [q-bio], BrisSynBio, RNA polymerase II, macromolecular substances, 03 medical and health sciences, Mice, 0302 clinical medicine, Transcription (biology), Intellectual Disability, Genetics, Animals, Humans, Molecular Biology, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, [SDV.GEN]Life Sciences [q-bio]/Genetics, General transcription factor, biology, Cell Death, Bristol BioDesign Institute, Homozygote, Promoter, Mouse Embryonic Stem Cells, General Medicine, Articles, Molecular biology, Disease Models, Animal, 030104 developmental biology, Blastocyst, Transcription Factor TFIID, Transcription preinitiation complex, Mutation, biology.protein, Microcephaly, Synthetic Biology, Drosophila, RNA Polymerase II, Transcription factor II D, TATA-binding protein, 030217 neurology & neurosurgery
Abstract: The human general transcription factor TFIID is composed of the TATA-binding protein (TBP) and 13 TBP-associated factors (TAFs). In eukaryotic cells, TFIID is thought to nucleate RNA polymerase II (Pol II) preinitiation complex formation on all protein coding gene promoters and thus, be crucial for Pol II transcription. In a child with intellectual disability, mild microcephaly, corpus callosum agenesis and poor growth, we identified a homozygous splice-site mutation in TAF8 (NM_138572.2: c.781-1G > A). Our data indicate that the patient's mutation generates a frame shift and an unstable TAF8 mutant protein with an unrelated C-terminus. The mutant TAF8 protein could not be detected in extracts from the patient's fibroblasts, indicating a loss of TAF8 function and that the mutation is most likely causative. Moreover, our immunoprecipitation and proteomic analyses show that in patient cells only partial TAF complexes exist and that the formation of the canonical TFIID is impaired. In contrast, loss of TAF8 in mouse embryonic stem cells and blastocysts leads to cell death and to a global decrease in Pol II transcription. Astonishingly however, in human TAF8 patient cells, we could not detect any cellular phenotype, significant changes in genome-wide Pol II occupancy and pre-mRNA transcription. Thus, the disorganization of the essential holo-TFIID complex did not affect global Pol II transcription in the patient's fibroblasts. Our observations further suggest that partial TAF complexes, and/or an altered TFIID containing a mutated TAF8, could support human development and thus, the absence of holo-TFIID is less deleterious for transcription than originally predicted.
Published: 2018

22. De novo and inherited private variants in MAP1B in periventricular nodular heterotopia

Author: Erin L Heinzen, Adam C O'Neill, Xiaolin Zhu, Andrew S Allen, Melanie Bahlo, Jamel Chelly, Ming Hui Chen, William B Dobyns, Saskia Freytag, Renzo Guerrini, Richard J Leventer, Annapurna Poduri, Stephen P Robertson, Christopher A Walsh, Mengqi Zhang, Epi4K Consortium, Epilepsy Phenome/Genome Project, univOAK, Archive ouverte, Columbia University Medical Center (CUMC), Columbia University [New York], University of Otago [Dunedin, Nouvelle-Zélande], Duke University Medical Center, Duke University [Durham], The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne, 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), Les Hôpitaux Universitaires de Strasbourg (HUS), Boston Children's Hospital, University of Washington [Seattle], Seattle Children's Research Institute [Seattle, WA, USA], Università degli Studi di Firenze = University of Florence (UniFI), Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), and Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]
Subjects: Male, 0301 basic medicine, Nonsynonymous substitution, Cancer Research, Heredity, [SDV.GEN] Life Sciences [q-bio]/Genetics, QH426-470, 0302 clinical medicine, Periventricular Nodular Heterotopia, Loss of Function Mutation, Epilepsy Phenome/Genome Project, Medicine and Health Sciences, Exome, Genetics (clinical), Exome sequencing, Genetics, Database and informatics methods, Sequence analysis, Brain, Genomics, Magnetic Resonance Imaging, Penetrance, 3. Good health, Fragile X syndrome, Genetic Mapping, Neurology, Female, Transcriptome Analysis, Microtubule-Associated Proteins, Research Article, Heterozygote, Bioinformatics, Variant Genotypes, Biology, 03 medical and health sciences, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, Allele, Molecular Biology, Alleles, DNA sequence analysis, Ecology, Evolution, Behavior and Systematics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Epilepsy, Biology and Life Sciences, Computational Biology, Human Genetics, Genome Analysis, medicine.disease, Perisylvian polymicrogyria, Research and analysis methods, 030104 developmental biology, Genetic Loci, 030217 neurology & neurosurgery
Abstract: Periventricular nodular heterotopia (PVNH) is a malformation of cortical development commonly associated with epilepsy. We exome sequenced 202 individuals with sporadic PVNH to identify novel genetic risk loci. We first performed a trio-based analysis and identified 219 de novo variants. Although no novel genes were implicated in this initial analysis, PVNH cases were found overall to have a significant excess of nonsynonymous de novo variants in intolerant genes (p = 3.27x10-7), suggesting a role for rare new alleles in genes yet to be associated with the condition. Using a gene-level collapsing analysis comparing cases and controls, we identified a genome-wide significant signal driven by four ultra-rare loss-of-function heterozygous variants in MAP1B, including one de novo variant. In at least one instance, the MAP1B variant was inherited from a parent with previously undiagnosed PVNH. The PVNH was frontally predominant and associated with perisylvian polymicrogyria. These results implicate MAP1B in PVNH. More broadly, our findings suggest that detrimental mutations likely arising in immediately preceding generations with incomplete penetrance may also be responsible for some apparently sporadic diseases., Author summary Almost 20 years ago the first gene responsible for periventricular nodular heterotopia (PVNH), a disorder that leads to abnormal migration of neurons during fetal brain development, was discovered. Since that time additional genes have been identified, but collectively they only explain a minority of cases. In this work we sought to further elucidate the genetic basis of this disorder using exome sequencing of 202 individuals with PVNH. We found a clear role for de novo mutations in PVNH, although with this analysis alone we were unable to pinpoint which of the de novo mutations in novel genes caused the disease. One patient was found to have a de novo variant in MAP1B, a gene that encodes a protein that plays a role at several key steps of brain development. With further analysis of the exome sequence data we found an additional three cases with a very rare inherited variant in MAP1B. This pattern is not expected to occur by chance and therefore indicates that these variants are likely responsible for the PVNH in these patients. Further strengthing the association of MAP1B in PVNH, all of the patients with a MAP1B variant had a similar brain abnormality, and at least one of the parents who transmitted the variant to their child was also similarly affected. This work adds to a growing list of genes responsible for PVNH, illuminates new genes involved in brain development, and importantly informs us about the types of genetic variants involved in PVNH.
Published: 2018

23. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Author: Kury, S., Woerden, G.M. van, Besnard, T., Onori, M.P., Latypova, X., Towne, M.C., Cho, M.T., Prescott, T.E., Ploeg, M.A., Sanders, S., Stessman, H.A.F., Pujol, A., Distel, ben, Robak, L.A., Bernstein, J.A., Denomme-Pichon, A.S., Lesca, G., Sellars, E.A., Berg, J., Carre, W., Busk, O.L., Bon, B.W.M. van, Waugh, J.L., Deardorff, M., Hoganson, G.E., Bosanko, K.B., Johnson, D.S., Dabir, T., Holla, O.L., Sarkar, A., Tveten, K., Bellescize, J. de, Braathen, G.J., Terhal, P.A., Grange, D.K., Haeringen, A. van, Lam, C., Mirzaa, G., Burton, J., Bhoj, E.J., Douglas, J., Santani, A.B., Nesbitt, A.I., Helbig, K.L., Andrews, M.V., Begtrup, A., Tang, S., Gassen, K.L.I. van, Juusola, J., Foss, K., Enns, G.M., Moog, U., Hinderhofer, K., Paramasivam, N., Lincoln, S., Kusako, B.H., Lindenbaum, P., Charpentier, E., Nowak, C.B., Cherot, E., Simonet, T., Ruivenkamp, C.A.L., Hahn, S., Brownstein, C.A., Xia, F., Schmitt, S., Deb, W., Bonneau, D., Nizon, M., Quinquis, D., Chelly, J., Rudolf, G., Sanlaville, D., Parent, P., Gilbert-Dussardier, B., Toutain, A., Sutton, V.R., Thies, J., Peart-Vissers, L.E.L.M., Boisseau, P., Vincent, M., Grabrucker, A.M., Dubourg, C., Tan, W.H., Verbeek, N.E., Granzow, M., Santen, G.W.E., Shendure, J., Isidor, B., Pasquier, L., Redon, R., Yang, Y.P., State, M.W., Kleefstra, T., Cogne, B., Petrovski, S., Retterer, K., Eichler, E.E., Rosenfeld, J.A., Agrawal, P.B., Bezieau, S., Odent, S., Elgersma, Y., Mercier, S., Undiagnosed Dis Network, GEM HUGO, Deciphering Dev Dis Study, Service de génétique médicale [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Neuroscience [Rotterdam, the Netherlands], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Expertise Center for Neurodevelopmental Disorders [Rotterdam, the Netherlands] (ENCORE), Genomics Program and Division of Genetics [Boston, USA], Harvard Medical School [Boston] (HMS)-Boston Children's Hospital-The Manton Center for Orphan Disease Research, Gene Discovery Core [Boston, MA, USA] ( The Manton Center for Orphan Disease Research), Harvard Medical School [Boston] (HMS)-Boston Children's Hospital, GeneDx [Gaithersburg, MD, USA], Department of Medical Genetics [Skien, Norway], Telemark Hospital Trust [Skien, Norway], Department of Psychiatry [San Francisco, CA, USA], University of California [San Francisco] (UCSF), University of California-University of California, Department of Genome Sciences [Seattle] (GS), University of Washington [Seattle], Department of Pharmacology [Omaha, NE, USA], Creighton University Medical School [Omaha, NE, USA], Neurometabolic Diseases Laboratory [Barcelona, Spain], Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Centre for Biomedical Research on Rare Diseases [Barcelona, Spain] (CIBERER), Hospital Sant Joan de Déu [Barcelona], Institució Catalana de Recerca i Estudis Avançats (ICREA), Department of Medical Biochemistry [Amsterdam, the Netherlands] (Academic Medical Center), University of Amsterdam [Amsterdam] (UvA), Department of Molecular and Human Genetics [Houston, USA], Baylor College of Medecine, Department of Pediatrics [Stanford], Stanford Medicine, Stanford University-Stanford University, Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Service de Génétique [HCL, Lyon] (Centre de Référence des Anomalies du Développement), Hospices civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Section of Genetics and Metabolism [Little Rock, AR, USA], University of Arkansas for Medical Sciences (UAMS), Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Laboratoire de Génétique Moléculaire & Génomique [CHU Rennes], CHU Pontchaillou [Rennes], Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Pediatrics [Philadelphia, PA, USA] (Division of Genetics), Children’s Hospital of Philadelphia (CHOP ), Department of Pediatrics [Chicago, IL, USA] (College of Medicine), University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Sheffield Children's NHS Foundation Trust, Northern Ireland Regional Genetics Centre [Belfast, UK], Belfast City Hospital-Belfast Health and Social Care Trust, Nottingham Regional Genetics Service [Nottingham, UK], City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], Département d'Epilepsie, Sommeil et Neurophysiologie Pédiatrique [HCL, Lyon], Hospices Civils de Lyon (HCL), Department of Genetics [Utrecht, the Netherlands], University Medical Center [Utrecht], Department of Pediatrics [Saint Louis, MO, USA] (Division of Genetics and Genomic Medicine), Washington University in Saint Louis (WUSTL), Department of Clinical Genetics [Leiden, the Netherlands], Leiden University Medical Center (LUMC), Department of Pediatrics [Seattle, WA, USA] (Division of Genetic Medicine), University of Washington [Seattle]-Seattle Children’s Hospital, Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, The Center for Applied Genomics [Philadelphia, PA, USA], Division of Human Genetics [Philadelphia, PA, USA], Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA], University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA] (Perelman School of Medicine), Division of Clinical Genomics [Aliso Viejo, CA, USA], Ambry Genetics [Aliso Viejo, CA, USA], Division of Neurology [Philadelphia, PA, USA], Institute of Human Genetics [Heidelberg, Germany], Universität Heidelberg [Heidelberg], University of Heidelberg, Medical Faculty, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Service de Neurologie [CHU Strasbourg], Hôpital de Hautepierre [Strasbourg]-Centre Hospitalier Universitaire de Strasbourg (CHU de Strasbourg ), Département de génétique médicale en pédiatrie [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de Génétique [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de Génétique [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Department of Biological Sciences [Limerick, Ireland], University of Limerick (UL), Bernal Institute [Limerick, Ireland], Howard Hughes Medical Institute [Seattle], Howard Hughes Medical Institute (HHMI), Institut de Génétique et Développement de Rennes (IGDR), 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), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de Génétique Clinique [CHU Rennes] (Réseau de Génétique et Génomique Médicale), Hôpitaux Universitaires du Grand Ouest, The Wellcome Trust Sanger Institute [Cambridge], Department of Medicine [Melbourne, Australia], University of Melbourne-Austin Health, Division of Newborn Medicine [Boston, MA, USA], Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Neurosciences, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Univ Angers, Okina, University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], Universiteit Leiden-Universiteit Leiden, Department of Pediatrics [Seattle, WA, USA], University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, Universität Heidelberg [Heidelberg] = Heidelberg University, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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 ), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Amsterdam Gastroenterology Endocrinology Metabolism, Medical Biochemistry, and Bernardo, Elizabeth
Subjects: 0301 basic medicine, Male, de novo mutations, AMPAR, medicine.disease_cause, Inbred C57BL, Mice, 0302 clinical medicine, Intellectual disability, CAMK2A, Exome, Phosphorylation, Genetics (clinical), Genetics, Neurons, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Brain, Phenotype, NMDAR, intellectual disability, Female, Signal transduction, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Signal Transduction, Glutamic Acid, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, Cell Line, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Journal Article, Animals, Humans, Protein kinase A, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], synaptic plasticity, medicine.disease, Mice, Inbred C57BL, CAMK2, CAMK2B, 030104 developmental biology, HEK293 Cells, Synaptic plasticity, Calcium-Calmodulin-Dependent Protein Kinase Type 2, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Contains fulltext : 182539.pdf (Publisher’s version ) (Closed access) Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.
Published: 2017

24. Postzygotic inactivating mutations of RHOA cause a mosaic neuroectodermal syndrome

Author: M. Elizabeth Ross, Philippine Garret, Jean Benoît Courcet, Guillaume Captier, Francesca Faravelli, Michèle Mathieu-Dramard, Veronica A. Kinsler, Bernard Devauchelle, Bénédicte Demeer, David Geneviève, S.S. Kholmanskikh, Odile Boute, Christel Thauvin, Satyamaanasa Polubothu, Paul Kuentz, Julien Thevenon, Esther Carmi, Arnaud Lafon, William B. Dobyns, Yannis Duffourd, Geneviève Bernard, Judith St-Onge, Laurence Faivre, Jean Baptiste Rivière, Arthur Sorlin, Pierre Vabres, Catherine Gondry-Jouet, Alain Bron, Didier Bessis, V. Carmignac, Laurent Guibaud, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Weill Cornell Medicine, CHU Amiens-Picardie, McGill University = Université McGill [Montréal, Canada], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Centre Hospitalier Universitaire de Lille (CHU de Lille), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Université Bourgogne Franche-Comté [COMUE] (UBFC), Dermatology Office, Hospices Civils de Lyon (HCL), Seattle Children’s Research Institute, Montreal Children’s Hospital, University College of London [London] (UCL), This work was funded by the Agence Nationale de la Recherche (grant no. ANR-13-PDOC-0029 to J.-B.R.), the Programme Hospitalier de Recherche Clinique National 2010 (grant no. NCT01950975 to P.V.), the NIH (grant no. HD067244 to M.E.R.) and the Societe Francaise de Dermatologie. G.B. has received a Research Scholar Junior 1 (2012-2016) salary award from the Fonds de Recherche du Quebec en Sante and the New Investigator salary award (2017-2022) from the Canadian Institute for Health Research (no. MOP-G-287547, file no. 24805)., ProdInra, Migration, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, and Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement
Subjects: RHOA, Zygote, Skin Pigmentation, Disease, Article, Leukoencephalopathy, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, 030304 developmental biology, Hypopigmentation, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Extramural, Mosaicism, Neurocutaneous Syndromes, medicine.disease, 3. Good health, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Mutation, Etiology, Cancer research, biology.protein, medicine.symptom, rhoA GTP-Binding Protein, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Hypopigmentation along Blaschko’s lines is a hallmark of a poorly defined group of mosaic syndromes whose genetic causes are unknown. Here we show that postzygotic inactivating mutations of RHOA cause a neuroectodermal syndrome combining linear hypopigmentation, alopecia, apparently asymptomatic leukoencephalopathy, and facial, ocular, dental, and acral anomalies. Our findings pave the way towards elucidating the etiology of pigmentary mosaicism and highlight the role of RHOA in human development and disease., Editorial summary Postzygotic inactivating mutations in RHOA cause a mosaic neuroectodermal syndrome characterized by linear hypopigmentation, leukoencephalopathy, and craniofacial anomalies, highlighting the role of RHOA in human development and disease.
Published: 2016

25. Burden of disease and costs of exposure to endocrine disrupting chemicals in the European Union: an updated analysis

Author: Martine Bellanger, Russ Hauser, Jerrold J. Heindel, N E Skakkebaek, Sheela Sathyanarayana, Andreas Kortenkamp, P M Hunt, John Peterson Myers, Juliette Legler, Joseph DiGangi, Ruthann A. Rudel, Leonardo Trasande, Philippe Grandjean, R. T. Zoeller, Ulla Hass, Dpt of Population Health [New York], New York University School of Medicine, NYU System (NYU)-NYU System (NYU), College of Global Public Health [New York], New York University [New York] (NYU), Departments of Pediatrics and Environmental Medicine [New York], Department of Biology, University of Massachusetts System (UMASS), Laboratoire de Géologie de Lyon - Terre, Planètes, Environnement [Lyon] (LGL-TPE), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon), Psychopharmacology Unit, University of Bristol [Bristol], Scuola universitaria professionale della Svizzera italiana [Manno] (SUPSI), Seattle Children's Research Institute, École des Hautes Études en Santé Publique [EHESP] (EHESP), EA Management des Organisations de Santé (EA MOS), École des Hautes Études en Santé Publique [EHESP] (EHESP)-PRES Sorbonne Paris Cité, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), and Scuola universitaria professionale della Svizzera italiana = University of Applied Sciences and Arts of Southern Switzerland [Manno] (SUPSI)
Subjects: 0301 basic medicine, Endocrine Disruptors/economics, Urology, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Sciences, Disease, Endocrine Disruptors, Childhood obesity, Article, economic costs, disease burden, Paediatrics and Reproductive Medicine, 03 medical and health sciences, Endocrinology, SDG 3 - Good Health and Well-being, Theoretical, Cost of Illness, Models, Economic cost, Environmental health, Intellectual disability, Genetics, Medicine, media_common.cataloged_instance, Humans, European Union, Causation, European union, Endocrine disrupting chemicals, Disease burden, media_common, business.industry, Environmental Exposure, Models, Theoretical, medicine.disease, endocrine disrupting chemicals, 3. Good health, 030104 developmental biology, Reproductive Medicine, Economic costs, Life course approach, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Monte Carlo Method, Environmental Exposure/adverse effects
Abstract: A previous report documented that endocrine disrupting chemicals contribute substantially to certain forms of disease and disability. In the present analysis, our main objective was to update a range of health and economic costs that can be reasonably attributed to endocrine disrupting chemical exposures in the European Union, leveraging new burden and disease cost estimates of female reproductive conditions from accompanying report. Expert panels evaluated the epidemiologic evidence, using adapted criteria from the WHO Grading of Recommendations Assessment, Development and Evaluation Working Group, and evaluated laboratory and animal evidence of endocrine disruption using definitions recently promulgated by the Danish Environmental Protection Agency. The Delphi method was used to make decisions on the strength of the data. Expert panels consensus was achieved for probable (>20%) endocrine disrupting chemical causation for IQ loss and associated intellectual disability; autism; attention deficit hyperactivity disorder; endometriosis; fibroids; childhood obesity; adult obesity; adult diabetes; cryptorchidism; male infertility, and mortality associated with reduced testosterone. Accounting for probability of causation, and using the midpoint of each range for probability of causation, Monte Carlo simulations produced a median annual cost of €163 billion (1.28% of EU Gross Domestic Product) across 1000 simulations. We conclude that endocrine disrupting chemical exposures in the EU are likely to contribute substantially to disease and dysfunction across the life course with costs in the hundreds of billions of Euros per year. These estimates represent only those endocrine disrupting chemicals with the highest probability of causation; a broader analysis would have produced greater estimates of burden of disease and costs. © 2016 American Society of Andrology and European Academy of Andrology A previous report documented that endocrine disrupting chemicals contribute substantially to certain forms of disease and disability. In the present analysis, our main objective was to update a range of health and economic costs that can be reasonably attributed to endocrine disrupting chemical exposures in the European Union, leveraging new burden and disease cost estimates of female reproductive conditions from accompanying report. Expert panels evaluated the epidemiologic evidence, using adapted criteria from the WHO Grading of Recommendations Assessment, Development and Evaluation Working Group, and evaluated laboratory and animal evidence of endocrine disruption using definitions recently promulgated by the Danish Environmental Protection Agency. The Delphi method was used to make decisions on the strength of the data. Expert panels consensus was achieved for probable (>20%) endocrine disrupting chemical causation for IQ loss and associated intellectual disability; autism; attention deficit hyperactivity disorder; endometriosis; fibroids; childhood obesity; adult obesity; adult diabetes; cryptorchidism; male infertility, and mortality associated with reduced testosterone. Accounting for probability of causation, and using the midpoint of each range for probability of causation, Monte Carlo simulations produced a median annual cost of €163 billion (1.28% of EU Gross Domestic Product) across 1000 simulations. We conclude that endocrine disrupting chemical exposures in the EU are likely to contribute substantially to disease and dysfunction across the life course with costs in the hundreds of billions of Euros per year. These estimates represent only those endocrine disrupting chemicals with the highest probability of causation; a broader analysis would have produced greater estimates of burden of disease and costs.
Published: 2016

26. The International Collaboration on Air Pollution and Pregnancy Outcomes: Initial Results

Author: Eun-Hee Ha, Angela Cecilia Pesatori, Ulrike Gehring, Rémy Slama, Michelle L. Bell, Rachel Morello-Frosch, Paolo Grillo, Michael Brauer, Bin Jalaludin, Johanna Lepeule, Svetlana V. Glinianaia, Frank H. Pierik, Daniel Wartenberg, Ju Hee Seo, Jong Han Leem, Tracey J. Woodruff, Lyndsey A. Darrow, Lillian Tamburic, Jennifer D. Parker, David Q. Rich, Sheela Sathyanarayana, Geoffrey G. Morgan, Matthew J. Strickland, Edith H. van den Hooven, Matteo Bonzini, Nelson Gouveia, Bill M. Jesdale, Centers for Disease Control and Prevention, National Center for Health Statistics, Department of Community and Preventive Medicine, University of Rochester School of Medicine and Dentistry, Institute of Health and Society, Newcastle University [Newcastle], Department of Occupational & Environmental Medicine, Inha University, UMDNJ-Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, Rutgers University System (Rutgers)-Rutgers University System (Rutgers), Yale University School of Medicine, Department of Experimental Medicine, Universitá degli Studi dell’Insubria, University of British Columbia (UBC), Department of Environmental Health, Emory University [Atlanta, GA], Risk Assessment Sciences Institute, Utrecht University [Utrecht], Department of Preventive Medicine, School of Medicine, University of São Paulo (USP), Epidemiology Unite, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Department of Preventive Medicine, EWHA Womans University (EWHA), The Generation R Study Group, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Environment and Health, The Netherlands Organisation for Applied Scientific Research (TNO), North Coast Area Health Service, Centre for Research, Evidence Management and Surveillance, University of New South Wales [Sydney] (UNSW)-Sydney South West Area Health Service-School of Public Health and Community Medicine, Department of Environmental Science, Policy, and Management [Berkeley] (ESPM), University of California [Berkeley], University of California-University of California, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), School of Public Health, University of California, Northern Rivers University Department of Rural Health, The University of Sydney, INSERM U823, équipe 12 (Epidémiologie Environnementale appliquée à la Reproduction et la Santé Respiratoire), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Department of Occupational and Environmental Health, Università degli Studi di Milano [Milano] (UNIMI), Seattle Children's Research Institute, Centre for Health Services and Policy Research, Center for Reproductive Health and the Environment, and Dr. Bell was supported, in part, by NIH 1R01ES016317. Dr. Lepeule by a post-doctoral grant from Inserm. Dr. Gehring was supported by a research fellowship of the Netherlands Organization for Scientific Research (NWO).
Subjects: Research design, QUALIDADE DO AR, MESH: Premature Birth, International Cooperation, Health, Toxicology and Mutagenesis, air pollution, adverse effects/statistics /&/ numerical data, Pilot Projects, 010501 environmental sciences, Toxicology, Particulate Matter Pregnancy, Medical and Health Sciences, 01 natural sciences, Cohort Studies, MESH: Pregnancy, 0302 clinical medicine, MESH: Risk Factors, 2.5 Research design and methodologies (aetiology), Risk Factors, Pregnancy, Infant Mortality, Medicine and Health Sciences, Medicine, 030212 general & internal medicine, Aetiology, MESH: Cohort Studies, Pediatric, MESH: Research Design, MESH: Infant, Newborn, Pregnancy Outcome, 3. Good health, 2.5 Research design and methodologies, MESH: Particulate Matter, Research Design, UES - Urban Environment & Safety, Air Pollution, adverse effects/statistics /&/ numerical data, Birth Weight, Cohort Studies, Feasibility Studies, Female, Humans, Infant, Low Birth Weight, Infant, Newborn, International Cooperation, Particle Size, Particulate Matter, analysis/toxicity, Pilot Projects, Pregnancy, Pregnancy Outcome, Premature Birth, chemically induced/epidemiology, Research Design, Risk Factors, Socioeconomic Factors, Premature Birth, Term Birth, Female, EELS - Earth, Environmental and Life Sciences, medicine.symptom, Cohort study, MESH: Air Pollution, MESH: Socioeconomic Factors, Earth & Environment, Birth weight, Air pollution, MESH: Infant, Low Birth Weight, Environment, Article, 03 medical and health sciences, Clinical Research, Environmental health, Humans, Climate-Related Exposures and Conditions, MESH: Particle Size, low birth weight, MESH: Birth Weight, Particle Size, analysis/toxicity, 0105 earth and related environmental sciences, particulate matter, MESH: Humans, business.industry, Prevention, ICAPPO, Infant, Newborn, Public Health, Environmental and Occupational Health, Infant, birth weight, Odds ratio, Perinatal Period - Conditions Originating in Perinatal Period, Infant, Low Birth Weight, MESH: Pilot Projects, MESH: Pregnancy Outcome, Newborn, Confidence interval, MESH: International Cooperation, Low birth weight, Socioeconomic Factors, 13. Climate action, Relative risk, chemically induced/epidemiology, Feasibility Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Feasibility Studies, Particulate matter, business, MESH: Female, Environmental Sciences
Abstract: International audience; BACKGROUND: The findings of prior studies of air pollution effects on adverse birth outcomes are difficult to synthesize because of differences in study design. OBJECTIVES: The International Collaboration on Air Pollution and Pregnancy Outcomes was formed to understand how differences in research methods contribute to variations in findings. We initiated a feasibility study to a) assess the ability of geographically diverse research groups to analyze their data sets using a common protocol and b) perform location-specific analyses of air pollution effects on birth weight using a standardized statistical approach. METHODS: Fourteen research groups from nine countries participated. We developed a protocol to estimate odds ratios (ORs) for the association between particulate matter ≤ 10 μm in aerodynamic diameter (PM₁₀) and low birth weight (LBW) among term births, adjusted first for socioeconomic status (SES) and second for additional location-specific variables. RESULTS: Among locations with data for the PM₁₀ analysis, ORs estimating the relative risk of term LBW associated with a 10-μg/m³ increase in average PM₁₀ concentration during pregnancy, adjusted for SES, ranged from 0.63 [95% confidence interval (CI), 0.30-1.35] for the Netherlands to 1.15 (95% CI, 0.61-2.18) for Vancouver, with six research groups reporting statistically significant adverse associations. We found evidence of statistically significant heterogeneity in estimated effects among locations. CONCLUSIONS: Variability in PM₁₀-LBW relationships among study locations remained despite use of a common statistical approach. A more detailed meta-analysis and use of more complex protocols for future analysis may uncover reasons for heterogeneity across locations. However, our findings confirm the potential for a diverse group of researchers to analyze their data in a standardized way to improve understanding of air pollution effects on birth outcomes.
Published: 2011

27. Quantitative trait loci affecting the 3D skull shape and size in mouse and prioritization of candidate genes in-silico

Author: Michael L. Cunningham, Timothy C. Cox, Nicolas Navarro, A. Murat Maga, Division of Craniofacial Medicine, University of Washington [Seattle], Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Laboratoire PALEVO, École pratique des hautes études ( EPHE ), Biogéosciences [Dijon] ( BGS ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Department of Anatomy and Developmental Biology, Monash University [Clayton], NIH/NIDCR Pathways to Independence award (5K99DE021417-02), Conseil Régional de Bourgogne funding (Grant #CRB PARI Agrale 5 Faber 2014-9201AAO047S01518), Laurel Foundation Endowment for Craniofacial Research (TCC),Jean Renny Endowment for Craniofacial Research (MCM)., Laboratoire Paléobiodiversité et Evolution (PALEVO), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Biogéosciences [UMR 6282] [Dijon] (BGS), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)
Subjects: Candidate gene, Physiology, Single-nucleotide polymorphism, Biology, Quantitative trait locus, lcsh:Physiology, [ SDV.BDD.MOR ] Life Sciences [q-bio]/Development Biology/Morphogenesis, Family-based QTL mapping, 3D imaging, Physiology (medical), medicine, geometric morphometrics, skull shape, Original Research, Genetics, Morphometrics, Autosome, lcsh:QP1-981, food and beverages, [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis, [ SDV.GEN.GA ] Life Sciences [q-bio]/Genetics/Animal genetics, multivariate QTL mapping, candidate gene enrichment, Skull, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, medicine.anatomical_structure, Neurocranium
Abstract: 13 pages; International audience; We describe the first application of high-resolution 3D micro-computed tomography, together with 3D landmarks and geometric morphometrics, to map QTL responsible for variation in skull shape and size using a backcross between C57BL/6J and A/J inbred strains. Using 433 animals, 53 3D landmarks, and 882 SNPs from autosomes, we identified seven QTL responsible for the skull size (SCS.qtl) and 30 QTL responsible for the skull shape (SSH.qtl). Size, sex, and direction-of-cross were all significant factors and included in the analysis as covariates. All autosomes harbored at least one SSH.qtl, sometimes up to three. Effect sizes of SSH.qtl appeared to be small, rarely exceeding 1% of the overall shape variation. However, they account for significant amount of variation in some specific directions of the shape space. Many QTL have stronger effect on the neurocranium than expected from a random vector that will parcellate uniformly across the four cranial regions. On the contrary, most of QTL have an effect on the palate weaker than expected. Combined interval length of 30 SSH.qtl was about 315 MB and contained 2476 known protein coding genes. We used a bioinformatics approach to filter these candidate genes and identified 16 high-priority candidates that are likely to play a role in the craniofacial development and disorders. Thus, coupling the QTL mapping approach in model organisms with candidate gene enrichment approaches appears to be a feasible way to identify high-priority candidates genes related to the structure or tissue of interest.
Published: 2015

28. The Transcription Factor Encyclopedia

Author: Yusuf, Dimas, Butland, Stefanie L., Swanson, Magdalena I., Bolotin, Eugene, Ticoll, Amy, Cheung, Warren A., Zhang, Xiao Yu Cindy, Dickman, Christopher T. D., Fulton, Debra L., Lim, Jonathan S., Schnabl, Jake M., Ramos, Oscar H. P., Vasseur-Cognet, Mireille, de Leeuw, Charles N., Simpson, Elizabeth M., Ryffel, Gerhart U., Lam, Eric W.-F., Kist, Ralf, Wilson, Miranda S. C., Marco-Ferreres, Raquel, Brosens, Jan J., Beccari, Leonardo L., Bovolenta, Paola, Benayoun, Bérénice A., Monteiro, Lara J, Schwenen, Helma D C, Grontved, Lars, Wederell, Elizabeth, Mandrup, Susanne, Veitia, Reiner A, Chakravarthy, Harini, Hoodless, Pamela A., Mancarelli, M Michela, Torbett, Bruce E, Banham, Alison H, Reddy, Sekhar P, Cullum, Rebecca L, Liedtke, Michaela, Tschan, Mario P, Vaz, Michelle, Rizzino, Angie, Zannini, Mariastella, Frietze, Seth, Farnham, Peggy J, Eijkelenboom, Astrid, Brown, Philip J, Laperrière, David, Leprince, Dominique, de Cristofaro, Tiziana, Prince, Kelly L, Putker, Marrit, del Peso, Luis, Camenisch, Gieri, Wenger, Roland H, Mikula, Michal, Rozendaal, Marieke, Mader, Sylvie, Ostrowski, Jerzy, Rhodes, Simon J, Van Rechem, Capucine, Boulay, Gaylor, Olechnowicz, Sam W Z, Breslin, Mary B, Lan, Michael S, Nanan, Kyster K, Wegner, Michael, Hou, Juan, Mullen, Rachel D, Colvin, Stephanie C, Noy, Peter John, Webb, Carol F, Witek, Matthew E, Ferrell, Scott, Daniel, Juliet M, Park, Jason, Waldman, Scott A, Peet, Daniel J, Taggart, Michael, Jayaraman, Padma-Sheela, Karrich, Julien J, Blom, Bianca, Vesuna, Farhad, O'Geen, Henriette, Sun, Yunfu, Gronostajski, Richard M, Woodcroft, Mark W, Hough, Margaret R, Chen, Edwin, Europe-Finner, G Nicholas, Karolczak-Bayatti, Magdalena, Bailey, Jarrod, Hankinson, Oliver, Raman, Venu, LeBrun, David P, Biswal, Shyam, Harvey, Christopher J, DeBruyne, Jason P, Hogenesch, John B, Hevner, Robert F, Héligon, Christophe, Luo, Xin M, Blank, Marissa Cathleen, Millen, Kathleen Joyce, Sharlin, David S, Forrest, Douglas, Dahlman-Wright, Karin, Zhao, Chunyan, Mishima, Yuriko, Sinha, Satrajit, Chakrabarti, Rumela, Portales-Casamar, Elodie, Sladek, Frances M, Bradley, Philip H, Wasserman, Wyeth W, Cindy Zhang, Xiao, Department of Medical Genetics, Faculty of Medicine-Child and Family Research Institute-Centre for Molecular Medicine and Therapeutics-University of British Columbia (UBC), Evaluation and Research Services, Fraser Health Authority, Children's Hospital Oakland, Oakland Research Institute, Computational Biology Program, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Department of Bioinformatics, Child and Family Research Institute-Centre for Molecular Medicine and Therapeutics-University of British Columbia (UBC), Department of Biology, University of Western Ontario (UWO), Genetics Program, Department of Cell Biology and Neuroscience [Riverside] (CBNS), University of California [Riverside] (UC Riverside), University of California (UC)-University of California (UC), Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 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), Institut für Zellbiologie, Universität Duisburg-Essen [Essen]-Universitätsklinikum Essen, Department of Surgery and Cancer, Imperial College London-Division of Cancer, Centre for Oral Health Research, Newcastle University [Newcastle]-Medical School-School of Dental Sciences, Department of Development and Differentiation, Centro de Biología Molecular Severo Ochoa [Madrid] (CBMSO), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-CIBER de Enfermedades Raras (CIBERER), Division of Reproductive Health, University of Warwick [Coventry]-Warwick Medical School, University of Warwick [Coventry], Neurobiologia Molecular Celular y del desarrollo, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Department of Biochemistry and Molecular Biology, University of Southern Denmark (SDU), Terry Fox Laboratory, BC Cancer Agency (BCCRC)-Provincial Health Services Authority, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, University of Nebraska System-University of Nebraska System, Department of Molecular Experimental Medicine, The Scripps Research Institute [La Jolla, San Diego], Departments of Molecular and Experimental Medicine and Immunology and Microbial Sciences (MEM 131), Nuffield Department of Clinical Laboratory Sciences, University of Oxford- John Radcliffe Hospital [Oxford University Hospital]-Oxford NIHR Biomedical Research Centre, Department of Pediatrics, College of Medicine-Department of pediatrics-University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Division of Hematology [Stanford], Stanford Medicine, Stanford University-Stanford University, Department of Medicine, University of Bern, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine [Baltimore]-Johns Hopkins University School of Medicine [Baltimore]-Johns Hopkins University School of Medicine, Institute of Experimental Endocrinology and Oncology (IEOS), Consiglio Nazionale delle Ricerche (CNR), University of Southern California (USC)-Norris Comprehensive Cancer Center, Department of Molecular Cancer Research, University Medical Center [Utrecht]-Utrecht University [Utrecht], University of Oxford- John Radcliffe Hospital [Oxford University Hospital]-Medical Sciences Division, Molecular Targeting in Breast Cancer research unit, Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM)-Université de Montréal (UdeM), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indiana University System-Indiana University System, Department of Physiological Chemistry, Department of Biochemistry, Universidad Autónoma de Madrid (UAM)-School of Medicine, Institute of Physiology, Universität Zürich [Zürich] = University of Zurich (UZH)-Zurich Center for Integrative Human Physiology, Department of Oncological Genetics, Institute of Oncology-Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC)-Medical Center of Postgraduate Education [Warsaw] (MCPE), Indiana University [Bloomington], Indiana University System-Indiana University System-School of Science, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston]-Cancer Center, University of Adelaide-School of Molecular and Biomedical Science, Department of Pediatrics and Biochemistry and Molecular Biology, Louisiana State University (LSU)-Research Institute for Children-Children's Hospital at New Orleans, Departments of Pediatrics and Genetics, Department of Pathology and Molecular Medicine, Queen's University [Kingston, Canada]-Queen's Cancer Research Institute, School of Medicine [Erlangen], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU)-Institut fuer Biochemie-Emil-Fischer-Zentrum, Department of Molecular Biology and Biochemistry, University Indianapolis-Indiana University School of Medicine, Department of Immunity and Infection, School of Medical and Dental Sciences-University of Birmingham [Birmingham], Immunobiology and Cancer Program, Oklahoma Medical Research Foundation (OMRF), Radiation Oncology, Department of Pharmacology and Experimental Therapeutics-Jefferson University Hospitals, Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center (OUHSC), McMaster University [Hamilton, Ontario], School of Medicine, Johns Hopkins University (JHU), Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University-Jefferson Medical College, Discipline of Biochemistry, Institute of Cellular Medicine, Newcastle University [Newcastle]-Faculty of Medicine-Medical School, Department of Immunity and Immunology, Department of Cell Biology and Histology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Center for Immunology Amsterdam, Division of Cancer Imaging Research, Johns Hopkins University (JHU)-School of Medicine-Department of Radiology, Genome Center [UC Davis], University of California [Davis] (UC Davis), School of Biological Sciences [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), Department of Biochemistry and Developmental Genomics Group, University at Buffalo [SUNY] (SUNY Buffalo), State University of New York (SUNY)-State University of New York (SUNY)-Center of Excellence in Bioinformatics and Life Sciences, Department of Molecular and Cellular Biology, University of Toronto-Sunnybrook Health Sciences Centre-Department of Laboratory Medicine and Pathobiology, Faculty of Medical Sciences, Newcastle University [Newcastle]-Medical School-Institute of Cellular Medicine, Department of Pathology and Laboratory Medicine, University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Radiology and Oncology, Johns Hopkins University (JHU)-School of Medicine, Department of Environmental Health Sciences, Johns Hopkins University (JHU)-Johns Hopkins Bloomberg School of Public Health [Baltimore], Department of Pharmacology and Toxicology, Neuroscience Institute-Morehouse School of Medicine, Department of Pharmacology, University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, Department of Neurological Surgery, University of Washington [Seattle]-Seattle Children's Research Institute, Faculty of Biology and Medicine, Université de Lausanne = University of Lausanne (UNIL)-Center for Integrated Genomics, Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University [Blacksburg]-Virginia-Maryland College of Veterinary Medicine, Department of Molecular Genetics and Cell Biology, University of Illinois [Chicago] (UIC), Center for Integrative Brain Research, University of Washington [Seattle], Clinical Endocrinology Branch, National Institutes of Health (NIH)-National Institute of Diabetes, Digestive, and Kidney Disorders, Department of Biosciences and Nutrition, Karolinska Institutet [Stockholm], State University of New York (SUNY)-State University of New York (SUNY), BMC, Ed., Universität Duisburg-Essen = University of Duisburg-Essen [Essen]-Universitätsklinikum Essen, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), UAM. Departamento de Bioquímica, Faculty of Medicine-Child and Family Research Institute-Centre for Molecular Medicine and Therapeutics-University of British Columbia ( UBC ), Fred Hutchinson Cancer Research Center [Seattle] ( FHCRC ) -Public Health Sciences Division, Child and Family Research Institute-Centre for Molecular Medicine and Therapeutics-University of British Columbia ( UBC ), University of Western Ontario ( UWO ), Department of Cell Biology and Neuroscience [Riverside] ( CBNS ), University of California [Riverside] ( UCR ), Service d'Ingénierie Moléculaire des Protéines ( SIMOPRO ), Département Médicaments et Technologies pour la Santé ( DMTS ), Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Institut Cochin ( 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 ), CIBER de Enfermedades Raras (CIBERER)-Consejo Superior de Investigaciones Científicas [Spain] ( CSIC ) -Centro de Biologia Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas [Spain] ( CSIC ) -Centro de Biologia Molecular Severo Ochoa (CBMSO)-CIBER de Enfermedades Raras (CIBERER), Service de Pathologies moléculaire et cellulaire, Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), UNIVERSITY OF SOUTHERN DENMARK, BC Cancer Agency ( BCCRC ) -Provincial Health Services Authority, Scripps Research Institute, Departments of Molecular and Experimental Medicine and Immunology and Microbial Sciences ( MEM 131 ), University of Oxford [Oxford]- John Radcliffe Hospital [Oxford University Hospital]-Oxford NIHR Biomedical Research Centre, College of Medicine-Department of pediatrics-University of Illinois at Chicago ( UIC ), Department of Medicine/Hematology, Stanford University School of Medicine, Institute of Experimental Endocrinology and Oncology ( IEOS ), CNR - National Research Council, University of Southern California ( USC ) -Norris Comprehensive Cancer Center, Utrecht University [Utrecht]-University Medical Center Utrecht, University of Oxford [Oxford]- John Radcliffe Hospital [Oxford University Hospital]-Medical Sciences Division, Université de Montréal-Institute for Research in Immunology and Cancer, Institut de biologie de Lille - IBL ( IBLI ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Lille, Droit et Santé, Utrecht University [Utrecht]-University Medical Centre Utrecht, Universidad Autonoma de Madrid ( UAM ) -School of Medicine, University of Zürich [Zürich] ( UZH ) -Zurich Center for Integrative Human Physiology, Institute of Oncology-Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology ( MCMCC ) -Medical Center of Postgraduate Education [Warsaw] ( MCPE ), Indiana University [Bloomington]-School of Science, Harvard Medical School [Boston] ( HMS ) -Cancer Center-Massachusetts General Hospital, Louisiana State University Health Sciences Center-Research Institute for Children-Children's Hospital at New Orleans, Queen's University [Kingston]-Queen's Cancer Research Institute, Institut fuer Biochemie-Emil-Fischer-Zentrum-Friedrich-Alexander Universitaet Erlangen-Nuernberg, Indiana University School of Medicine-University Indianapolis, Oklahoma Medical Research Foundation, Department of Pharmacology and Experimental Therapeutics-Jefferson University Hospital, University of Oklahoma Health Sciences Center ( OUHSC ), Johns Hopkins University ( JHU ), Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ) -University of Amsterdam [Amsterdam] ( UvA ) -Center for Immunology Amsterdam, Johns Hopkins University ( JHU ) -School of Medicine-Department of Radiology, University of California at Davis, Division of Biological Sciences [San Diego], University of California [San Diego] ( UC San Diego ), State University of New York at Buffalo ( SUNY Buffalo ) -Center of Excellence in Bioinformatics and Life Sciences, University of California at Los Angeles [Los Angeles] ( UCLA ) -David Geffen School of Medicine, Johns Hopkins University ( JHU ) -School of Medicine, Johns Hopkins University ( JHU ) -Johns Hopkins Bloomberg School of Public Health, University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Lausanne-Center for Integrated Genomics, Virginia Polytechnic Institute and State University [Blacksburg]-VA-MD Regional College of Veterinary Medicine, University of Illinois at Chicago ( UIC ), State University of New York at Buffalo ( SUNY Buffalo ) -University of Buffalo School of Medicine and Biomedical Sciences, University of California [Riverside] (UCR), University of California-University of California, Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-CIBER de Enfermedades Raras (CIBERER), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Johns Hopkins University School of Medicine-The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine [Baltimore]-Johns Hopkins University School of Medicine [Baltimore], Utrecht University [Utrecht]-University Medical Center [Utrecht], Universidad Autonoma de Madrid (UAM)-School of Medicine, Cancer Center-Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU)-Emil-Fischer-Zentrum-Institut fuer Biochemie, School of Molecular and Biomedical Science-University of Adelaide, School of Medicine-Department of Radiology-Johns Hopkins University (JHU), University of California-University of California-David Geffen School of Medicine [Los Angeles], Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU)-Johns Hopkins University (JHU), University of Pennsylvania [Philadelphia], Université de Lausanne (UNIL)-Center for Integrated Genomics, AII - Amsterdam institute for Infection and Immunity, and Cell Biology and Histology
Subjects: Encyclopedias as Topic, INFORMATION, WIKI, Transcription, Genetic, 05 Environmental Sciences, Medizin, [SDV.GEN] Life Sciences [q-bio]/Genetics, Automate Content, Web API, ANNOTATION, Mini review, Mice, 0302 clinical medicine, Portable Document Format, GENETICS & HEREDITY, Databases, Protein, Informática, 0303 health sciences, PROTEIN DATA-BANK, Application programming interface, BIOTECHNOLOGY & APPLIED MICROBIOLOGY, MENDELIAN-INHERITANCE, ddc:57, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030220 oncology & carcinogenesis, Application Programming Interface, Encyclopedia, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], The Internet, Transcription (software), Transcription, Life Sciences & Biomedicine, KNOWLEDGEBASE, Medicina, DATABASE, Bioinformatics, Biology, Medizinische Fakultät » Universitätsklinikum Essen » Institut für Zellbiologie (Tumorforschung), World Wide Web, Access to Information, 03 medical and health sciences, Databases, Genetic, Protein Data Bank, ddc:570, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], ddc:61, Animals, Humans, ddc:610, MeSH Term, Transcription factor, 030304 developmental biology, Internet, 08 Information And Computing Sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, GENE-REGULATION, business.industry, Protein, Computational Biology, 06 Biological Sciences, Compendium, EVOLUTION, Rats, Evolutionary biology, UPDATE, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Software, Transcription Factors
Abstract: Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.
Published: 2012

29. The International Collaboration on Air Pollution and Pregnancy Outcomes: initial results

Author: Parker, Jennifer, Rich, David, Glinianaia, Svetlana, Leem, Jong Han, Wartenberg, Daniel, Bell, Michelle, Bonzini, Matteo, Brauer, Michael, Darrow, Lyndsey, Gehring, Ulrike, Gouveia, Nelson, Grillo, Paolo, Ha, Eunhee, van den Hooven, Edith, Jalaludin, Bin, Jesdale, Bill, Lepeule, Johanna, Morello-Frosch, Rachel, Morgan, Geoffrey, Slama, Rémy, Pierik, Frank, Pesatori, Angela Cecilia, Sathyanarayana, Sheela, Seo, Juhee, Strickland, Matthew, Tamburic, Lillian, Woodruff, Tracey, Centers for Disease Control and Prevention, National Center for Health Statistics, Department of Community and Preventive Medicine, University of Rochester School of Medicine and Dentistry, Institute of Health and Society, Newcastle University [Newcastle], Department of Occupational & Environmental Medicine, Inha University, UMDNJ-Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, Rutgers University System (Rutgers)-Rutgers University System (Rutgers), Yale School of Medicine [New Haven, Connecticut] (YSM), Department of Experimental Medicine, Universitá degli Studi dell’Insubria = University of Insubria [Varese] (Uninsubria), University of British Columbia (UBC), Department of Environmental Health, Emory University [Atlanta, GA], Risk Assessment Sciences Institute, Utrecht University [Utrecht], Department of Preventive Medicine, School of Medicine, Universidade de São Paulo = University of São Paulo (USP), Epidemiology Unite, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Department of Preventive Medicine, EWHA Womans University (EWHA), The Generation R Study Group, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Environment and Health, The Netherlands Organisation for Applied Scientific Research (TNO), North Coast Area Health Service, Centre for Research, Evidence Management and Surveillance, University of New South Wales [Sydney] (UNSW)-Sydney South West Area Health Service-School of Public Health and Community Medicine, Department of Environmental Science, Policy, and Management [Berkeley] (ESPM), University of California [Berkeley] (UC Berkeley), University of California (UC)-University of California (UC), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), School of Public Health, University of California (UC), Northern Rivers University Department of Rural Health, The University of Sydney, INSERM U823, équipe 12 (Epidémiologie Environnementale appliquée à la Reproduction et la Santé Respiratoire), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Occupational and Environmental Health, Università degli Studi di Milano = University of Milan (UNIMI), Seattle Children's Research Institute, Centre for Health Services and Policy Research, Center for Reproductive Health and the Environment, Dr. Bell was supported, in part, by NIH 1R01ES016317. Dr. Lepeule by a post-doctoral grant from Inserm. Dr. Gehring was supported by a research fellowship of the Netherlands Organization for Scientific Research (NWO)., and Slama, Rémy
Subjects: MESH: Air Pollution, MESH: Socioeconomic Factors, MESH: Humans, MESH: Premature Birth, ICAPPO, MESH: Research Design, MESH: Infant, Newborn, Low Birth Weight, MESH: Infant, Low Birth Weight, MESH: Pilot Projects, MESH: Pregnancy Outcome, Particulate Matter Pregnancy, MESH: International Cooperation, MESH: Pregnancy, MESH: Particulate Matter, MESH: Risk Factors, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Air Pollution, Birth Weight, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Particle Size, MESH: Birth Weight, MESH: Feasibility Studies, MESH: Cohort Studies, MESH: Female
Abstract: International audience; BACKGROUND: The findings of prior studies of air pollution effects on adverse birth outcomes are difficult to synthesize because of differences in study design. OBJECTIVES: The International Collaboration on Air Pollution and Pregnancy Outcomes was formed to understand how differences in research methods contribute to variations in findings. We initiated a feasibility study to a) assess the ability of geographically diverse research groups to analyze their data sets using a common protocol and b) perform location-specific analyses of air pollution effects on birth weight using a standardized statistical approach. METHODS: Fourteen research groups from nine countries participated. We developed a protocol to estimate odds ratios (ORs) for the association between particulate matter ≤ 10 μm in aerodynamic diameter (PM₁₀) and low birth weight (LBW) among term births, adjusted first for socioeconomic status (SES) and second for additional location-specific variables. RESULTS: Among locations with data for the PM₁₀ analysis, ORs estimating the relative risk of term LBW associated with a 10-μg/m³ increase in average PM₁₀ concentration during pregnancy, adjusted for SES, ranged from 0.63 [95% confidence interval (CI), 0.30-1.35] for the Netherlands to 1.15 (95% CI, 0.61-2.18) for Vancouver, with six research groups reporting statistically significant adverse associations. We found evidence of statistically significant heterogeneity in estimated effects among locations. CONCLUSIONS: Variability in PM₁₀-LBW relationships among study locations remained despite use of a common statistical approach. A more detailed meta-analysis and use of more complex protocols for future analysis may uncover reasons for heterogeneity across locations. However, our findings confirm the potential for a diverse group of researchers to analyze their data in a standardized way to improve understanding of air pollution effects on birth outcomes.
Published: 2011

30. The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis

Author: Gerhard Kluger, Laurence E. Walsh, Eva Klopocki, Dagmar Wieczorek, Soma Das, Sulagna C. Saitta, Amy Goldstein, Kerstin Kutsche, Max Flindt, Anita Rauch, Agathe Roumer, Fanny Kortüm, Gökhan Uyanik, Deborah J. Morris-Rosendahl, P. Martin, Irina Stefanova, Denise Horn, William B. Dobyns, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), University of Chicago, University Clinic Freiburg, Universität zu Lübeck [Lübeck], Children's Hospital of Pittsburgh, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Epilepsy Center for Children and Adolescents, Epilepsy Center Kork, Epilepsy Center Kork = Epilepsiezentrum Kork, Allergy Unit - Department of Dermatology, Universität Zürich [Zürich] = University of Zurich (UZH), Sozialpädiatrisches Zentrum Frankfurt Mitte, Children’s Hospital of Philadelphia (CHOP ), Indiana University, Indiana University [Bloomington], Indiana University System-Indiana University System, Universitätsklinikum Essen, Seattle Children's Research Institute, University of Zurich, and Kutsche, K
Subjects: Male, Microcephaly, 10039 Institute of Medical Genetics, Methyl-CpG-Binding Protein 2, 610 Medizin, Medizin, Postnatal microcephaly, Corpus callosum, Corpus Callosum, 0302 clinical medicine, Medizinische Fakultät, Child, Genetics (clinical), Sequence Deletion, Genetics, 0303 health sciences, ddc:610, Comparative Genomic Hybridization, Forkhead Transcription Factors, Phenotype, Child, Preschool, Medical genetics, Female, 2716 Genetics (clinical), medicine.medical_specialty, Genotype, Molecular Sequence Data, 610 Medicine & health, Rett syndrome, Nerve Tissue Proteins, Biology, Article, MECP2, 03 medical and health sciences, 1311 Genetics, Intellectual Disability, medicine, Rett Syndrome, Humans, Clinical genetics, Genetic Association Studies, 030304 developmental biology, Chromosomes, Human, Pair 14, Dyskinesias, Base Sequence, Corpus Callosum Agenesis, medicine.disease, Developmental disorder, Molecular Typing, Mutation, 570 Life sciences, biology, 030217 neurology & neurosurgery
Abstract: Background Submicroscopic deletions in 14q12 spanning FOXG1 or intragenic mutations have been reported in patients with a developmental disorder described as a congenital variant of Rett syndrome. This study aimed to further characterise and delineate the phenotype of FOXG1 mutation positive patients. Method The study mapped the breakpoints of a 2;14 translocation by fluorescence in situ hybridisation and analysed three chromosome rearrangements in 14q12 by cytogenetic analysis and/or array comparative genomic hybridisation. The FOXG1 gene was sequenced in 210 patients, including 129 patients with unexplained developmental disorders and 81 MECP2 mutation negative individuals. Results One known mutation, seen in two patients, and nine novel mutations of FOXG1 including two deletions, two chromosome rearrangements disrupting or displacing putative cis -regulatory elements from FOXG1 , and seven sequence changes, are reported. Analysis of 11 patients in this study, and a further 15 patients reported in the literature, demonstrates a complex constellation of features including mild postnatal growth deficiency, severe postnatal microcephaly, severe mental retardation with absent language development, deficient social reciprocity resembling autism, combined stereotypies and frank dyskinesias, epilepsy, poor sleep patterns, irritability in infancy, unexplained episodes of crying, recurrent aspiration, and gastro-oesophageal reflux. Brain imaging studies reveal simplified gyral pattern and reduced white matter volume in the frontal lobes, corpus callosum hypogenesis, and variable mild frontal pachgyria. Conclusions These findings have significantly expanded the number of FOXG1 mutations and identified two affecting possible cis -regulatory elements. While the phenotype of the patients overlaps both classic and congenital Rett syndrome, extensive clinical evaluation demonstrates a distinctive and clinically recognisable phenotype which the authors suggest designating as the FOXG1 syndrome.
Published: 2011

31. Standardising health history and injury surveillance of participants in endurance events: a modified Delphi consensus statement from the AMSSM runner health consortium.

Author: Tenforde AS, Kraus E, Kliethermes SA, Fontana MA, Barrack MT, Dubon M, Heikura IA, Hollander K, Kroshus E, Joachim MR, Lopes AD, Rauh MJ, Chastain R, Harrast M, Heiderscheit B, Krabak BJ, Miller EM, Napier C, Roberts WO, Roche D, Roche M, Schroeder AN, Taylor-Douglas D, Tenforde K, Verhagen E, Warden SJ, Willy RW, and Toresdahl BG
Abstract: Endurance events are popular worldwide and have many health benefits. However, runners and Para athletes may sustain musculoskeletal injuries or experience other health consequences from endurance events. The American Medical Society for Sports Medicine (AMSSM) Runner Health Consortium aimed to generate consensus-based survey items for use in prospective research to identify risk factors for injuries in runners and Para athletes training and competing in endurance events. The study design employed a modified Delphi approach, with a panel comprising 28 experts, including healthcare professionals, coaches, and athletes. Potential survey items were generated by panel members who subsequently engaged in three rounds of voting using Research Electronic Data Capture. Items were graded by clarity, relevance, and importance. Items achieving 80% consensus on all three aspects were retained. The response rate was 100% in R round 1 and 96% in Rrounds 2 and 3. Of 124 initial survey items, consensus was reached on 53, 34 and 22 items during Rrounds 1, 2, and 3, respectively. Two accepted items were removed due to redundancy. Combined with 10 non-voting items, 117 items covered key domains, including training and injury history, dietary behaviours and associated factors (such as menstrual function), footwear, mental health, and specific considerations for Para athletes. The consensus-based survey items should be considered by researchers to better understand the health of runners and Para athletes who train and compete in endurance sports to identify risk factors for injury., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Published: 2024
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32. Candidacy Decisions for Long-term Ventilation.

Author: Vo HH, Keegan D, Sveen WN, Wilfond BS, Campelia G, and Henderson CM
Abstract: Decisions to initiate long-term ventilation (LTV) in children with severe neurologic impairment have recently been subject to candidacy determinations by home ventilation teams that exclude patients based on their neurologic status alone. Determinations of whether decisions are inappropriate require careful analysis of specific clinical circumstances and attention to the family's values. In this Ethics Rounds, we present a case of a previously healthy child who sustained an acute severe anoxic brain injury and was assessed by the medical team to have a high likelihood of remaining minimally conscious or unconscious. It was determined that he was not a candidate for LTV based on the severity of neurologic impairment. The family disagreed and declined withdrawal of ventilatory support. Drawing upon our backgrounds in intensive care, pulmonology, and bioethics, we offer commentary on utilizing a candidacy-based approach for LTV decisions in children with severe neurologic impairment from variable perspectives, including clinical determinations of inappropriate care, ablest biases and discrimination, and obligations to maintain a just process., Competing Interests: CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no conflicts of interest relevant to this article to disclose., (Copyright © 2024 by the American Academy of Pediatrics.)
Published: 2024
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33. An arylsulfonamide that targets cell wall biosynthesis in Mycobacterium tuberculosis .

Author: Allen R, Ames L, Baldin VP, Butts A, Henry KJ, Durst G, Quach D, Sugie J, Pogliano J, and Parish T
Subjects: Humans, Hep G2 Cells, Mycolic Acids metabolism, Membrane Transport Proteins metabolism, Membrane Transport Proteins genetics, Reactive Oxygen Species metabolism, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis genetics, Mycobacterium tuberculosis metabolism, Cell Wall drug effects, Cell Wall metabolism, Sulfonamides pharmacology, Antitubercular Agents pharmacology, Bacterial Proteins genetics, Bacterial Proteins metabolism, Microbial Sensitivity Tests
Abstract: We investigated the mechanism of action of an arylsulfonamide with whole-cell activity against Mycobacterium tuberculosis . We newly synthesized the molecule and confirmed it had activity against both extracellular and intracellular bacilli. The molecule had some activity against HepG2 cells but maintained some selectivity. Bacterial cytological profiling suggested that the mechanism of action was via disruption of cell wall synthesis, with similarities to an inhibitor of the mycolic acid exporter MmpL3. The compound induced expression from the IniB promoter and caused a boost in ATP production but did not induce reactive oxygen species. A mutation in MmpL3 (S591I) led to low-level resistance. Taken together, these data confirm the molecule targets cell wall biosynthesis with MmpL3 as the most probable target., Competing Interests: The authors declare no conflict of interest.
Published: 2024
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34. Scientists swarm into Woods Hole for the 10th Kinetoplastid Molecular Cell Biology Meeting.

Author: Keroack C, Cosentino RO, Teixeira TL, Lansink L, Larcombe SD, Davidge B, Serra L, de Graffenried C, Figueiredo LM, Harb OS, and Povelones ML
Abstract: Competing Interests: Declaration of interests The authors declare no competing interests.
Published: 2024
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35. Evaluation of a Modified Vesikari Severity Score as a Research Tool for Assessing Pediatric Acute Gastroenteritis.

Author: Wikswo ME, Weinberg GA, Szilagyi PG, Selvarangan R, Harrison CJ, Klein EJ, Englund JA, Sahni LC, Boom JA, Halasa NB, Stewart LS, Staat MA, Schlaudecker EP, Azimi PH, Johnston SH, and Mirza SA
Subjects: Humans, Acute Disease, Child, Child, Preschool, Female, Male, Infant, Absenteeism, Gastroenteritis diagnosis, Severity of Illness Index
Abstract: A modified Vesikari severity score (MVSS) is a useful research tool for assessing severity of acute gastroenteritis. We present a MVSS for studies in which a follow-up assessment of symptoms cannot be obtained. The MVSS significantly correlated with other markers of severity, including illness duration and work and school absenteeism., (Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society 2024.)
Published: 2024
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36. Developmental control of rod number via a light-dependent retrograde pathway from intrinsically photosensitive retinal ganglion cells.

Author: D'Souza SP, Upton BA, Eldred KC, Glass I, Nayak G, Grover K, Ahmed A, Nguyen MT, Hu YC, Gamlin P, and Lang RA
Subjects: Animals, Humans, Mice, Light, Rod Opsins metabolism, Rod Opsins genetics, Apoptosis, Retina metabolism, Retina cytology, Retinal Ganglion Cells metabolism, Retinal Ganglion Cells cytology, Retinal Rod Photoreceptor Cells metabolism
Abstract: Photoreception is essential for the development of the visual system, shaping vision's first synapse to cortical development. Here, we find that the lighting environment controls developmental rod apoptosis via Opn4-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs). Using genetics, sensory environment manipulations, and computational approaches, we establish a pathway where light-dependent glutamate released from ipRGCs is detected via a transiently expressed glutamate receptor (Grik3) on rod precursors within the inner retina. Communication between these cells is mediated by hybrid neurites on ipRGCs that sense light before eye opening. These structures span the ipRGC-rod precursor distance over development and contain the machinery for photoreception (Opn4) and neurotransmitter release (Vglut2 & Syp). Assessment of the human gestational retina identifies conserved hallmarks of an ipRGC-to-rod axis, including displaced rod precursors, transient GRIK3 expression, and ipRGCs with deep-projecting neurites. This analysis defines an adaptive retrograde pathway linking the sensory environment to rod precursors via ipRGCs prior to eye opening., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)
Published: 2024
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37. Afferent and Efferent Connections of the Postinspiratory Complex (PiCo) Revealed by AAV and Monosynaptic Rabies Viral Tracing.

Author: Oliveira LM, Huff A, Wei A, Miranda NC, Wu G, Xu X, and Ramirez JM
Subjects: Animals, Mice, Medulla Oblongata cytology, Medulla Oblongata virology, Afferent Pathways physiology, Mice, Transgenic, Male, Neuroanatomical Tract-Tracing Techniques, Vesicular Glutamate Transport Protein 2 metabolism, Vesicular Glutamate Transport Protein 2 genetics, Respiratory Center cytology, Respiratory Center physiology, Mice, Inbred C57BL, Rabies virus genetics, Efferent Pathways physiology, Dependovirus genetics
Abstract: The control of the respiratory rhythm and airway motor activity is essential for life. Accumulating evidence indicates that the postinspiratory complex (PiCo) is crucial for generating behaviors that occur during the postinspiratory phase, including expiratory laryngeal activity and swallowing. Located in the ventromedial medulla, PiCo is defined by neurons co-expressing two neurotransmitter markers (ChAT and Vglut2/Slc17a6). Here, we mapped the input-output connections of these neurons using viral tracers and intersectional viral-genetic tools. PiCo neurons were specifically targeted by focal injection of a doubly conditional Cre- and FlpO-dependent AAV8 viral marker (AAV8-Con/Fon-TVA-mCherry) into the left PiCo of adult Chat Cre/wt : Vglut2 FlpO/wt mice, for anterograde axonal tracing. These experiments revealed projections to various brain regions, including the Cu, nucleus of the solitary tract (NTS), Amb, X, XII, Sp5, RMg, intermediate reticular nucleus (IRt), lateral reticular nucleus (LRt), pre-Bötzinger complex (preBötC), contralateral PiCo, laterodorsal tegmental nucleus (LDTg), pedunculopontine tegmental nucleus (PPTg), periaqueductal gray matter (PAG), Kölliker-Fuse (KF), PB, and external cortex of the inferior colliculus (ECIC). A rabies virus (RV) retrograde transsynaptic approach was taken with EnvA-pseudotyped G-deleted (RV-SAD-G-GFP) to similarly target PiCo neurons in Chat Cre/wt : Vglut2 FlpO/wt mice, following prior injections of helper AAVs (a mixture of AAV-Ef1a-Con/Fon oG and viral vector AAV8-Con/Fon-TVA-mCherry). This combined approach revealed prominent synaptic inputs to PiCo neurons from NTS, IRt, and A1/C1. Although PiCo neurons project axons to the contralateral PiCo area, this approach did not detect direct contralateral connections. We suggest that PiCo serves as a critical integration site, projecting and receiving neuronal connections implicated in breathing, arousal, swallowing, and autonomic regulation., (© 2024 Wiley Periodicals LLC.)
Published: 2024
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38. Relational Space: How Setting of Care Changes the Content of Care for Young Adults.

Author: Lanphier E and Campelia GD
Published: 2024
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39. The impact of a whole foods dietary intervention on gastrointestinal symptoms, inflammation, and fecal microbiota in pediatric patients with cystic fibrosis: A pilot study.

Author: Green N, Miller C, Suskind D, Brown M, Pope C, Hayden H, McNamara S, Kanter A, Nay L, Hoffman L, and Rosenfeld M
Subjects: Humans, Pilot Projects, Child, Female, Male, Adolescent, Child, Preschool, Gastrointestinal Microbiome, Diet methods, Leukocyte L1 Antigen Complex analysis, Cystic Fibrosis microbiology, Cystic Fibrosis diet therapy, Cystic Fibrosis complications, Feces microbiology, Gastrointestinal Diseases diet therapy, Gastrointestinal Diseases microbiology, Inflammation diet therapy
Abstract: Background: Gastrointestinal (GI) complications are a significant source of morbidity for people with cystic fibrosis (PwCF). Historically, dietary recommendations in CF have focused on calories, typically emphasizing a high fat diet. The changing landscape of CF highlights the need to update this nutritional strategy. There is little research into how the quality of calories consumed by PwCF influences nutritional outcomes, GI symptoms, or likely contributors: intestinal inflammation and GI microbiology. We assessed the feasibility of a whole foods-based diet (WFD) and avoidance of ultra-processed foods, measuring safety/tolerability, adherence, and GI symptoms, as well as fecal measures of inflammation and microbiota among children with CF (CwCF) with GI symptoms., Methods: Single center, 4-week dietary intervention involving CwCF aged 5-14 years who screened positive on GI symptom questionnaire. Assessments included weight, symptom questionnaires and adverse events (AEs). Stool was analyzed for microbiota (16S rRNA) and calprotectin., Results: 108 children were pre-screened, 9 enrolled and 8 initiated and completed the study. There were no significant changes in weight and no AEs. PEDS-QL GI identified overall improvement in symptoms. Certain symptom domains (constipation, diarrhea, gas/bloating, stomach pain and hurt) demonstrated significant improvement on the WFD. Of two participants with abnormal fecal calprotectin at enrollment, both exhibited decreased values on WFD. There was no significant change in microbiota diversity., Conclusion: A WFD diet was feasible and safe in CwCF. There was improvement in GI symptom scores based on both parent and child assessments. Larger studies are needed to further investigate effects on intestinal inflammation and microbiota., Competing Interests: Conflict of interest The authors of this manuscript have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)
Published: 2024
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40. The Effects of Race, Primary Language, Insurance and Other Factors on Time to Pediatric Outpatient MRI Completion: A Retrospective Cohort Study.

Author: Noda SM, Alp Oztek M, Sullivan E, Otto RK, Stanford S, and Iyer RS
Subjects: Adolescent, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Ethnicity, Health Services Accessibility statistics & numerical data, Insurance, Health statistics & numerical data, Outpatients statistics & numerical data, Racial Groups, Retrospective Studies, Socioeconomic Factors, Time Factors, United States, Healthcare Disparities statistics & numerical data, Healthcare Disparities ethnology, Language, Magnetic Resonance Imaging statistics & numerical data
Abstract: Rationale and Objectives: Disparities in healthcare access in the United States have been associated with race and ethnicity, as well as socioeconomic factors. Because delays in imaging may result in delayed diagnosis or clinical management, we are evaluating practices within our radiology department in hopes of decreasing disparities in access to imaging. The objective of this study is to determine the disparities in time to outpatient MRI scheduling and completion by race, ethnicity, primary language, socioeconomic status, insurance and other factors at a tertiary children's hospital., Methods: After Institutional Review Board approval, we retrospectively extracted data from all outpatient MRI exams completed at our center between 10/5/2020 and 8/31/2022. Collected data included sex, age, race/ethnicity, primary language, medical complexity, insurance type, address, need for anesthesia, ordering specialty, and order acuity. We determined times to MRI scheduling or completion using mixed effects Cox regression models and determined associations between unadjusted and fully adjusted models., Results: We analyzed 14,002 completed outpatient MRI orders from 9714 unique patients. 56.2% were White, 19.2% Hispanic, 8.4% Asian, 4.5% Black/African-American, 1.4% American Indian/Alaska Native, 0.7% Native Hawaiian/Pacific Islander, 5.7% two or more races/ethnicities, and 3.8% "Other." In fully adjusted models, there was no significant association between race/ethnicity and time to MRI scheduling and completion. In fully adjusted models, time to completion of MRI was slower among those with Medicaid (adjusted hazard ratio [95% confidence interval] of 0.92 [0.87, 0.98]), a primary language other than English (0.90 [0.82, 0.99]), non-complex chronic illness (0.72 [0.67, 0.79]), complex chronic illness (0.72 [0.67, 0.78]) and need for anesthesia (0.75 [0.71, 0.79])., Conclusion: At our tertiary children's hospital, time to completion of outpatient MRI was not associated with race, but was greater among those with Medicaid insurance, whose primary language was not English, and needing anesthesia. Advocating for faster prior authorization by Medicaid, utilizing our hospital's live interpreter phone number for scheduling, and incorporating greater child life support to decrease anesthesia use are considerations for decreasing these disparities, although surveying patients and families most impacted by these discrepancies will be important to identify the most promising interventions., Data Availability Statement: Data are not publicly available to preserve individuals' privacy due to IRB restrictions. Data may be available upon reasonable request by contacting the corresponding author., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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41. Using a Previsit Questionnaire for Initial Visits in a Pediatric Mitochondrial Clinic: Perspectives of Parents, a Specialty Physician, and a Clinical Coordinator.

Author: Sepulveda CJ, Walsh E, Carlin K, and Saneto RP
Subjects: Humans, Surveys and Questionnaires, Male, Female, Child, Child, Preschool, Infant, Adolescent, Pediatrics methods, Quality of Life psychology, Physicians psychology, Parents psychology, Mitochondrial Diseases therapy, Mitochondrial Diseases psychology, Mitochondrial Diseases diagnosis
Abstract: Objective: In this study, we assessed the usefulness of a previsit questionnaire for children who were referred for an initial evaluation in a mitochondrial subspecialty clinic. We explored the themes regarding parent's questions, concerns, and goals. We aimed to add to existing knowledge about the usefulness of previsit questionnaires in a pediatric specialty setting from the perspective of parents, the specialist, and the clinical coordinator. Method: We enrolled 25 patients and their parent(s) over 25 months. Questionnaires were completed by the parent(s), the clinical coordinator, and the mitochondrial specialist. Descriptive statistics and thematic analysis were used to summarize results. Results: Parental responses suggested that they are most concerned about their child's clinical problems, communication, language and developmental delays, disease progression and prognosis, understanding mitochondrial disease, quality of life, and physical challenges including muscle and energy problems. Parents felt the previsit questionnaire was very helpful for both the doctor and for themselves to be prepared for their visit. The specialist and the clinical coordinator also found it to be helpful. Parental comments suggested that they felt that writing down the story of their child's life was helpful for the provider, allowed time for reflection, and improved the appointment experience. Some felt it was a difficult or redundant activity. Conclusion: Parents were often pleased to complete the previsit questionnaire. This allowed them to highlight concerns and share information that they wanted the care team to know about their child. We revised the tool based on feedback from parents and the specialist and will continue to use it in our clinic., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Published: 2024
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42. Effect of joint hypermobility on outcomes of children with juvenile idiopathic arthritis.

Author: Black WR, Singleton J, Wang X, Harris JG, and Jones JT
Subjects: Humans, Female, Male, Child, Adolescent, Severity of Illness Index, Disease Progression, Range of Motion, Articular, Young Adult, Child, Preschool, Arthritis, Juvenile complications, Arthritis, Juvenile physiopathology, Joint Instability complications, Joint Instability physiopathology
Abstract: Background: Juvenile idiopathic arthritis (JIA) is common in pediatric rheumatology. Despite treatment, many patients experience persistent disease activity. Joint hypermobility (JH), defined by an excessive range of motion across multiple joints, is prevalent in children and adolescents and may influence disease outcomes in JIA., Objective: This study examines the impact of JH on symptoms in youth and young adults with JIA., Methods: Data were obtained from the PR-COIN network and included patients under 21 years old with a diagnosis of JIA. Patients with JIA and JH were matched with those having JIA-only based on age, sex assigned at birth, JIA subtype, and medication exposure. Clinical data, including disease activity measures, patient well-being, and pain ratings, were collected at baseline and follow-up visits., Results: The sample included 420 patients with JIA + JH and 2100 with JIA only. The JIA + JH group exhibited higher disease activity at baseline, more active arthritis joints, elevated physician global assessment of disease activity scores, and worse patient-reported well-being. These differences persisted over time. The JIA + JH group had a 19-20% greater likelihood of maintaining high disease activity scores and worsening over subsequent visits, indicating a significant impact of JH on disease progression., Conclusion: JH in youth with JIA is associated with higher and persistent disease activity, suggesting that JH significantly contributes to the disease burden in patients with JIA and should be considered in treatment strategies. Future research should further explore the mechanisms by which JH influences disease activity and investigate comprehensive management approaches to improve outcomes for this population. Key Points • Children with JIA and joint hypermobility (JH) exhibit significantly higher disease activity at baseline compared to those with JIA only, including more active arthritis joints and elevated physician global assessment scores. • The presence of JH in JIA patients is associated with poorer patient-reported well-being and higher overall disease activity scores, which persist over time despite treatment. • JIA + JH patients have a 19-20% greater likelihood of maintaining high disease activity and worsening over subsequent visits, indicating a significant impact of JH on disease progression. • The study suggests that JH should be considered an important clinical factor in the management of JIA, with targeted interventions needed to address the increased disease activity and improve overall patient outcomes., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)
Published: 2024
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43. Compassionate use trials and equitable access to variant-specific treatment for cystic fibrosis.

Author: Odem-Davis K and Taylor-Cousar JL
Abstract: Competing Interests: KO-D is an employee at the Cystic Fibrosis Therapeutics Development Network (CF TDN) Coordinating Center at Seattle Children's Research Institute, with salary indirectly supported through the Cystic Fibrosis Foundation (CFF). JLT-C reports, as a faculty at an institution that is part of the CF TDN, site or national principal investigator roles on studies for 4DMT, Vertex, and Eloxx; grant funding from the CFF and NIH; payments to the institution for clinical trial advisory efforts from Vertex and 4DMT; travel support to participate in CFF Board of Trustees meetings from the CFF; past payments as Chair of an AbbVie data monitoring committee; role as adult patient care representative to the CFF Board of Trustees; serving on the CFF's Clinical Research Executive Committee, CFF advisory board, Racial Justice Working Group, scientific advisory board for Emily's Entourage, ATS Scientific Grant Review Committee, the Respiratory Research Awards Committee, and the NHLBI Clinical Trials Study Section; oles as immediate past Chair of the CF TDN's Sexual Health, Reproduction and Gender Research-Working Group, and Co-Chair of the Heath Equity Team Science Awards study section; role as current Chair-Elect for the ATS International Conference Committee; and membership of the International Advisory Board of The Lancet Respiratory Medicine and the Editorial Board of the Journal of Cystic Fibrosis.
Published: 2024
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44. Improved detection of cystic fibrosis by the California Newborn Screening Program for all races and ethnicities.

Author: McGarry ME, Sciortino S, Graham S, Bishop T, and Gibb ER
Subjects: Female, Humans, Infant, Newborn, Male, California, Cohort Studies, Ethnicity, False Negative Reactions, Trypsinogen blood, Racial Groups, Cystic Fibrosis diagnosis, Cystic Fibrosis genetics, Cystic Fibrosis ethnology, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Neonatal Screening methods
Abstract: Background: Newborn screening (NBS) for cystic fibrosis (CF) is universal in the United States. Protocols vary but include an immunoreactive trypsinogen (IRT) level and CFTR variant panel. California CF NBS has a 3-step screening: IRT level, variant panel, and CFTR sequencing if only one variant identified on panel., Methods: This was a cohort study of infants with CF born in California (2007-2021) to examine racial and ethnic differences in having a false-negative NBS result for CF and at which step the false-negative occurred. We examined how different CFTR variant panels would improve detection of variants by race and ethnicity: original 39-variant panel, current 75-variant panel, and all 402 disease-causing CFTR variants in the CFTR2 database., Results: Of the 912 infants born in California with CF, 84 had a false-negative result: 38 due to low IRT level and 46 with a high IRT value (but incomplete variant detection). Asian (OR 6.3) and Black infants (OR 2.5) were more likely to have a false-negative screening result than non-Hispanic white infants. The majority of false-negative screening (but CF diagnosis) cases among American Indian/Native Alaskan and non-Hispanic White infants were due to low IRT levels. The majority of Asian and Hispanic infants with false-negative screening had no variants detected. Detection of two CFTR variants was improved with the 75-variant panel in Black, Hispanic, and non-Hispanic White infants and with the 402-variant panel in Black, Hispanic, non-Hispanic White, and other race infants., Conclusions: Larger CFTR panels in NBS improved the detection of CF in all races and ethnicities., (© 2024 Wiley Periodicals LLC.)
Published: 2024
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45. Influence of chronotype on pain incidence during early adolescence.

Author: Li R, Groenewald C, Tham SW, Rabbitts JA, Ward TM, and Palermo TM
Subjects: Humans, Male, Female, Adolescent, Incidence, Child, Sleep physiology, Pain Measurement methods, Surveys and Questionnaires, Chronotype, Pain epidemiology, Circadian Rhythm physiology
Abstract: Abstract: During adolescence major shifts in sleep and circadian systems occur with a notable circadian phase delay. Yet, the circadian influence on pain during early adolescence is largely unknown. Using 2 years of data from the Adolescent Brain Cognitive Development study, we investigated the impact of chronotype on pain incidence, moderate-to-severe pain, and multiregion pain 1 year later in U.S. adolescents. Based on the Munich ChronoType Questionnaire, chronotype was calculated as the midpoint between sleep onset and offset on free days, corrected for sleep debt over the week. Adolescents reported pain presence over the past month, and if present, rated pain intensity (0-10 numerical rating scale; ≥ 4 defined as moderate-to-severe pain) and body site locations (Collaborative Health Outcomes Information Registry Body Map; ≥2 regions defined as multiregion pain). Three-level random intercept logistic regression models were specified for each pain outcome, adjusting for baseline sociodemographic and developmental characteristics. Among 5991 initially pain-free adolescents (mean age 12.0 years, SD 0.7), the mean chronotype was 3:59 am (SD 97 minutes), and the 1-year incidence of pain, moderate-to-severe pain, and multiregion pain was 24.4%, 15.2%, and 13.5%, respectively. Each hour later chronotype at baseline was associated with higher odds of developing any pain (odds ratio [OR] = 1.06, 95% confidence interval [CI] = 1.01, 1.11), moderate-to-severe pain (OR = 1.10, 95% CI = 1.05-1.17), and multiregion pain (OR = 1.08, 95% CI = 1.02-1.14) during 1-year follow-up. In this diverse U.S. adolescent sample, later chronotype predicted higher incidence of new-onset pain., (Copyright © 2024 International Association for the Study of Pain.)
Published: 2024
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46. Known pathogenic gene variants and new candidates detected in sudden unexpected infant death using whole genome sequencing.

Author: Bard AM, Clark LV, Cosgun E, Aldinger KA, Timms A, Quina LA, Ferres JML, Jardine D, Haas EA, Becker TM, Pagan CM, Santani A, Martinez D, Barua S, McNutt Z, Nesbitt A, Mitchell EA, and Ramirez JM
Subjects: Humans, Female, Infant, Male, Infant, Newborn, Genetic Variation, Adult, Gene Frequency, Sudden Infant Death genetics, Sudden Infant Death pathology, Whole Genome Sequencing, Genetic Predisposition to Disease
Abstract: The purpose of this study is to gain insights into potential genetic factors contributing to the infant's vulnerability to Sudden Unexpected Infant Death (SUID). Whole Genome Sequencing (WGS) was performed on 144 infants that succumbed to SUID, and 573 healthy adults. Variants were filtered by gnomAD allele frequencies and predictions of functional consequences. Variants of interest were identified in 88 genes, in 64.6% of our cohort. Seventy-three of these have been previously associated with SIDS/SUID/SUDP. Forty-three can be characterized as cardiac genes and are related to cardiomyopathies, arrhythmias, and other conditions. Variants in 22 genes were associated with neurologic functions. Variants were also found in 13 genes reported to be pathogenic for various systemic disorders and in two genes associated with immunological function. Variants in eight genes are implicated in the response to hypoxia and the regulation of reactive oxygen species (ROS) and have not been previously described in SIDS/SUID/SUDP. Seventy-two infants met the triple risk hypothesis criteria. Our study confirms and further expands the list of genetic variants associated with SUID. The abundance of genes associated with heart disease and the discovery of variants associated with the redox metabolism have important mechanistic implications for the pathophysiology of SUID., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
Published: 2024
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47. The next frontier of continuous pulse oximetry de-implementation: Overcoming competing priorities.

Author: McDaniel LM, Kurtz A, and Bryan MA
Published: 2024
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48. Genetic variation in severe cystic fibrosis liver disease is associated with novel mechanisms for disease pathogenesis.

Author: Stonebraker JR, Pace RG, Gallins PJ, Dang H, Aksit MA, Faino AV, Gordon WW, MacParland S, Bamshad MJ, Gibson RL, Cutting GR, Durie PR, Wright FA, Zhou YH, Blackman SM, O'Neal WK, Ling SC, and Knowles MR
Subjects: Humans, Female, Male, Adult, Severity of Illness Index, Liver Diseases genetics, Child, Adolescent, alpha 1-Antitrypsin genetics, Young Adult, Hypertension, Portal genetics, Whole Genome Sequencing, Cystic Fibrosis genetics, Cystic Fibrosis complications, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract: Background and Aims: It is not known why severe cystic fibrosis (CF) liver disease (CFLD) with portal hypertension occurs in only ~7% of people with CF. We aimed to identify genetic modifiers for severe CFLD to improve understanding of disease mechanisms., Approach and Results: Whole-genome sequencing was available in 4082 people with CF with pancreatic insufficiency (n = 516 with severe CFLD; n = 3566 without CFLD). We tested ~15.9 million single nucleotide polymorphisms (SNPs) for association with severe CFLD versus no-CFLD, using pre-modulator clinical phenotypes including (1) genetic variant ( SERPINA1 ; Z allele) previously associated with severe CFLD; (2) candidate SNPs (n = 205) associated with non-CF liver diseases; (3) genome-wide association study of common/rare SNPs; (4) transcriptome-wide association; and (5) gene-level and pathway analyses. The Z allele was significantly associated with severe CFLD ( p = 1.1 × 10 -4 ). No significant candidate SNPs were identified. A genome-wide association study identified genome-wide significant SNPs in 2 loci and 2 suggestive loci. These 4 loci contained genes [significant, PKD1 ( p = 8.05 × 10 -10 ) and FNBP1 ( p = 4.74 × 10 -9 ); suggestive, DUSP6 ( p = 1.51 × 10 -7 ) and ANKUB1 ( p = 4.69 × 10 -7 )] relevant to severe CFLD pathophysiology. The transcriptome-wide association identified 3 genes [ CXCR1 ( p = 1.01 × 10 -6 ) , AAMP ( p = 1.07 × 10 -6 ), and TRBV24 ( p = 1.23 × 10 -5 )] involved in hepatic inflammation and innate immunity. Gene-ranked analyses identified pathways enriched in genes linked to multiple liver pathologies., Conclusion: These results identify loci/genes associated with severe CFLD that point to disease mechanisms involving hepatic fibrosis, inflammation, innate immune function, vascular pathology, intracellular signaling, actin cytoskeleton and tight junction integrity and mechanisms of hepatic steatosis and insulin resistance. These discoveries will facilitate mechanistic studies and the development of therapeutics for severe CFLD., (Copyright © 2024 American Association for the Study of Liver Diseases.)
Published: 2024
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49. Grief Trajectories of Bereaved Parents of Adolescents and Young Adults With Advanced Cancer: A Qualitative Analysis Using Phenomenology.

Author: Kingsley J, Taylor M, Bogetz JF, Trowbridge A, Rosenberg AR, and Barton KS
Subjects: Humans, Female, Adolescent, Male, Young Adult, Adult, Qualitative Research, Attitude to Death, Middle Aged, Adaptation, Psychological, Bereavement, Spirituality, Neoplasms psychology, Parents psychology, Grief
Abstract: Different parents grieve differently. However, research directed at understanding the important contextual or individual factors that influence the path each bereaved parent takes is lacking. In this qualitative analysis we seek to understand the array of bereaved parent experiences more completely. By deeply diving into one parent dyad using interpretive phenomenology analysis and situating that story within the conventional content analysis of 13 other bereaved parents of adolescents and young adults (AYAs) who died from advanced cancer, we illustrate the roles of religion/spirituality, maintaining a connection, and fulfilling parental roles as elements of grief processing. Clinicians and investigators should consider similar individualized approaches to understanding and supporting the grief experiences of bereaved parents before and after the death of a child., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Published: 2024
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50. Measuring perceived utility of genomic sequencing: Development and validation of the GENEtic Utility (GENE-U) scale for adult screening.

Author: Smith HS, Rubanovich CK, Robinson JO, Levchenko AN, Classen SA, Malek J, Buchanan AH, Biesecker B, Brothers KB, Wilfond BS, Rini C, Bloss CS, McGuire AL, and Knight SJ
Subjects: Humans, Adult, Female, Male, Middle Aged, Surveys and Questionnaires, Genomics methods, Aged, Young Adult, Reproducibility of Results, Genetic Testing methods, Psychometrics methods
Abstract: Purpose: As population-based screening programs to identify genetic conditions in adults using genomic sequencing (GS) are increasingly available, validated patient-centered outcome measures are needed to understand participants' experience. We aimed to develop and validate an instrument to assess the perceived utility of GS in the context of adult screening., Methods: Informed by a 5-domain conceptual model, we used a 5-step approach to instrument development and validation: (1) item writing, (2) cognitive testing, (3) pilot testing and item reduction, (4) psychometric testing, and (5) evaluation of construct validity. Adults undergoing risk-based or population-based GS who had received GS results as part of ongoing research studies participated in structured cognitive interviews and 2 rounds of surveys. After item pool refinement, we conducted an exploratory factor analysis and calculated Pearson correlations with related instruments., Results: We derived the 18-item Adult Screening version of the GENEtic Utility scale (total sum score α = .87). Mirroring the Pediatric Diagnostic version, the instrument has a 2-factor structure, including an Informational Utility subscale (14 items, α = .89) and an Emotional Utility subscale (4 items, α = .75). The Informational Utility subscale was strongly associated with empowerment and personal utility of GS. Correlations of the Emotional Utility subscale with psychosocial impact and anxiety and depression were weak to moderate., Conclusion: Initial psychometric testing of the Adult Screening GENEtic Utility scale demonstrates its promise, and additional validation in translational genomics research is warranted., Competing Interests: Conflict of Interest Dr Smith’s work has been funded by the NIH. She has received compensation as a consultant for Illumina, Inc and RTI International, unrelated to this work. Mr Buchanan has an equity stake in MeTree, Inc and You, Inc, unrelated to this work. Dr McGuire is a member of the Scientific Advisory Board for Nurture Genomics. All other authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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