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3. Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability

Author

Létard, Pascaline, Drunat, Séverine, Vial, Yoann, Duerinckx, Sarah, Ernault, Anais, Amram, Daniel, Arpin, Stéphanie, Bertoli, Marta, Busa, Tiffany, Ceulemans, Berten, Desir, Julie, Doco-Fenzy, Martine, Elalaoui, Siham Chafai, Devriendt, Koenraad, Faivre, Laurence, Francannet, Christine, Geneviève, Geneviève, Gitiaux, Cyril, Julia, Sophie, Lebon, Sébastien, Lubala, Toni, Mathieu-Dramard, Michèle, Maurey, Hélène, Metreau, Julia, Nasserereddine, Sanaa, Nizon, Mathilde, Pierquin, Geneviève, Pouvreau, Nathalie, Rivier-Ringenbach, Clothilde, Rossi, Massimiliano, Schaefer, Elise, Sznajer, Yves, Tunca, Yusuf, Guilmin Crepon, Sophie, Alberti, Corinne, Elmaleh-Bergès, Monique, Benzacken, Brigitte, Wollnick, Bernd, Woods, C Geoffrey, Rauch, Anita, El Ghouzzi, Vincent, Gressens, Pierre, Verloes, Alain, Passemard, Sandrine, Geneviève, David, Julia, Julia, Woods, C. Geoffrey, Mordel, S, Schaeffer, Stéphane, Dupas, S., Laville, Marie-Alice, Chapon, Françoise, Allouche, S., Mordel, Patrick, Dupas, Quentin, Reggiani, Claudio, Coppens, Sandra, Sekhara, Tayeb, Dimov, Ivan, Pichon, Bruno, Lufin, Nicolas, Addor, Marie-Claude, Belligni, Elga Fabia, Digilio, Maria Cristina, Faletra, Flavio, Ferrero, Giovanni Battista, Gérard, Marion, Isidor, Bertrand, Joss, Shelagh, Niel-Bütschi, Florence, Perrone, Maria Dolores, Petit, Florence, Renieri, Alessandra, Romana, Serge, Topa, Alexandra, Vermeesch, Joris Robert, Lenaerts, Tom, Casimir, Georges, Abramowicz, Marc, Bontempi, Gianluca, Vilain, Catheline, Deconinck, Nicolas, Smits, Guillaume, Université libre de Bruxelles (ULB), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Turin, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Institute for Maternal and Child Health - IRCCS 'Burlo Garofolo' [Trieste], Service de Génétique Clinique [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), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Queen Elizabeth University Hospital (Glasgow), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Università degli Studi di Siena = University of Siena (UNISI), Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sahlgrenska University Hospital [Gothenburg], Université Catholique de Louvain = Catholic University of Louvain (UCL), Universiteit Gent = Ghent University [Belgium] (UGENT), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital universitaire Robert-Debré [Paris], UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Unité fonctionnelle de génétique clinique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Antwerp (UA), Institut de Pathologie et Génétique [Gosselies] (I.P.G.), Service de Génétique, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Centre for Human Genetics, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-University Hospitals Leuven [Leuven], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Clermont-Ferrand, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service de génétique médicale, CHU Amiens-Picardie, Service Neuropédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre de Génétique Humaine, Université de Liège-CHU Liège, Service de pédiatre-Néonatologie, CH Villefranche s/Saone, 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), Hôpital de Hautepierre [Strasbourg], Medical Genetics, Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Service d'imagerie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Département de génétique, Allergy Unit - Department of Dermatology, University of Zürich [Zürich] (UZH), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Department of Biology [Utah], University of Utah, Laboratoire Evolution, Génomes et Spéciation (LEGS), Centre National de la Recherche Scientifique (CNRS), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de biochimie [CHU Caen], Signalisation, électrophysiologie et imagerie des lésions d’ischémie-reperfusion myocardique (SEILIRM), Département Génétique Médicale-Maternité, Université de Lorraine (UL), Center for Medical Genetics, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Department of Human Genetics, Radboud University Medical Center [Nijmegen], AI-lab, Vakgroep Computerwetenschappen, Universiteit Gent [Ghent], gerard, marion, Università degli studi di Torino = University of Turin (UNITO), Universiteit Gent = Ghent University (UGENT), and Informatics and Applied Informatics

Subjects
Male, 0301 basic medicine, Guanylate Kinases/genetics, Developmental Disabilities, Intellectual disability, lcsh:Medicine, ASPM, brain imaging, brain development, Tumor Suppressor Proteins -- genetics, Genome, Mice, Intellectual Disability -- genetics -- metabolism, Global developmental delay, Copy-number variation, Promoter Regions, Genetic, Child, Genetics (clinical), Epigenomics, Genetics, ATP6 deletion, Membrane Proteins -- genetics, primary microcephaly, Neurodevelopmental disorders, food and beverages, Functional genomics, Exons, DLG2, Promoters, Animals, Female, Guanylate Kinases, Humans, Intellectual Disability, Membrane Proteins, Tumor Suppressor Proteins, Molecular Medicine, Molecular Biology, Sciences bio-médicales et agricoles, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Guanylate Kinases -- genetics, lcsh:QH426-470, Developmental Disabilities/genetics, Developmental Disabilities/metabolism, Intellectual Disability/genetics, Intellectual Disability/metabolism, Membrane Proteins/genetics, Tumor Suppressor Proteins/genetics, Genomics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Promoter Regions, 03 medical and health sciences, Genetic, Complex V deficiency, Next generation sequencing, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene, MCPH, Developmental Disabilities -- genetics -- metabolism, Research, lcsh:R, Human genetics, Mitochondrial disease, lcsh:Genetics, 030104 developmental biology, centrosome, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, NARP syndrome
Abstract

Tissue-specific integrative omics has the potential to reveal new genic elements important for developmental disorders., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2017

4. Expanding Phenotype of Poirier-Bienvenu Syndrome: New Evidence from an Italian Multicentrical Cohort of Patients

Author

Alessandro Orsini, Andrea Santangelo, Francesca Bravin, Alice Bonuccelli, Diego Peroni, Roberta Battini, Thomas Foiadelli, Veronica Bertini, Angelo Valetto, Michele Iacomino, Vincenzo Nigro, Anna Laura Torella, Marcello Scala, Valeria Capra, Maria Stella Vari, Anna Fetta, Veronica Di Pisa, Francesca Montanari, Roberta Epifanio, Paolo Bonanni, Roberto Giorda, Francesca Operto, Grazia Pastorino, Esra Sarigecili, Esra Sardaroglu, Cetin Okuyaz, Sevgan Bozdogan, Luciana Musante, Flavio Faletra, Caterina Zanus, Alessandro Ferretti, Federico Vigevano, Pasquale Striano, Duccio Maria Cordelli, Orsini, Alessandro, Santangelo, Andrea, Bravin, Francesca, Bonuccelli, Alice, Peroni, Diego, Battini, Roberta, Foiadelli, Thoma, Bertini, Veronica, Valetto, Angelo, Iacomino, Michele, Nigro, Vincenzo, Torella, Anna Laura, Scala, Marcello, Capra, Valeria, Vari, Maria Stella, Fetta, Anna, Di Pisa, Veronica, Montanari, Francesca, Epifanio, Roberta, Bonanni, Paolo, Giorda, Roberto, Operto, Francesca, Pastorino, Grazia, Sarigecili, Esra, Sardaroglu, Esra, Okuyaz, Cetin, Bozdogan, Sevgan, Musante, Luciana, Faletra, Flavio, Zanus, Caterina, Ferretti, Alessandro, Vigevano, Federico, Striano, Pasquale, and Cordelli, Duccio Maria

Subjects
Pobind, CSNK2B, Epilepsy, Neurodevelopment, Pobinds, Seizure, neurodevelopment, Developmental Disabilitie, Developmental Disabilities, seizure, Syndrome, Phenotype, epilepsy, Retrospective Studie, Intellectual Disability, Genetics, Humans, Child, Genetics (clinical), Human, Retrospective Studies
Abstract

Background: Poirier–Bienvenu Neurodevelopmental Syndrome (POBINDS) is a rare disease linked to mutations of the CSNK2B gene, which encodes for a subunit of caseinkinase CK2 involved in neuronal growth and synaptic transmission. Its main features include early-onset epilepsy and intellectual disability. Despite the lack of cases described, it appears that POBINDS could manifest with a wide range of phenotypes, possibly related to the different mutations of CSNK2B. Methods: Our multicentric, retrospective study recruited nine patients with POBINDS, detected using next-generation sequencing panels and whole-exome sequencing. Clinical, laboratory, and neuroimaging data were reported for each patient in order to assess the severity of phenotype, and eventually, a correlation with the type of CSNK2B mutation. Results: We reported nine unrelated patients with heterozygous de novo mutations of the CSNK2B gene. All cases presented epilepsy, and eight patients were associated with a different degree of intellectual disability. Other features detected included endocrinological and vascular abnormalities and dysmorphisms. Genetic analysis revealed six new variants of CSNK2B that have not been reported previously. Conclusion: Although it was not possible to assess a genotype–phenotype correlation in our patients, our research further expands the phenotype spectrum of POBINDS patients, identifying new mutations occurring in the CSNK2B gene.

Published
2022

5. A case report of glucose transporter 1 deficiency syndrome with growth hormone deficiency diagnosed before starting ketogenic diet

Author

Flavio Faletra, Egidio Barbi, Giuseppa Patti, Elena Faleschini, Paola Costa, Maria Chiara Pellegrin, Gianluca Tornese, Tornese, Gianluca, Patti, Giuseppa, Pellegrin, MARIA CHIARA, Costa, Paola, Faletra, Flavio, Faleschini, Elena, and Barbi, Egidio

Subjects
Male, Microcephaly, Pediatrics, medicine.medical_specialty, Ataxia, CSF glucose, Monosaccharide Transport Proteins, medicine.medical_treatment, SLC2A1, Hypoglycemia, Short stature, Growth hormone deficiency, Case report, Ketogenic diet, Seizure, medicine, Humans, Child, Growth Disorders, Dystonia, business.industry, lcsh:RJ1-570, lcsh:Pediatrics, medicine.disease, Growth Hormone, medicine.symptom, business, Diet, Ketogenic, Carbohydrate Metabolism, Inborn Errors
Abstract

Background Growth failure and growth hormone deficiency (GHD) have been reported as one accessory feature of GLUT1 deficiency syndrome (GLUT1DS), considered so far as a long-term adverse effects of ketogenic diet which is used to treat this condition. Case presentation We report the case of a 10-year-old Caucasian boy referred for short stature (height − 2.56 SDS) and delayed growth (growth velocity − 4.33 SDS) who was diagnosed with GHD and started treatment with recombinant human growth hormone (rhGH). Because of his history of seizures with infantile onset, deceleration of head growth with microcephaly, ataxia, and moderate intellectual disability, a lumbar puncture was performed, which revealed a low CSF glucose concentration with a very low CSF-to-blood glucose ratio (SLC2A1 gene exon 1 deletion confirming a diagnosis of GLUT1DS. Ketogenic diet was started. After 5.5 years of rhGH treatment his height was normalized (− 1.15 SDS). No side effects were reported during treatment, particularly on glycemic metabolism. Conclusions This is the first case of GHD in a Caucasian boy with GLUT1DS diagnosed before starting ketogenic diet, with a good response to rhGH treatment and absence of side effects. We speculate that GHD may represent a poorly recognized clinical feature of GLUT1DS rather than a complication due to ketogenic diet. Under-diagnosis may derive from the fact that growth failure is usually ascribed to ketogenic diet and therefore not further investigated. Pediatric neurologists need to be alerted to the possible presence of GHD in patients with GLUT1DS with slow growth, while pediatric endocrinologist need to refer GHD patients with additional features (motor and cognitive developmental delay, seizures with infantile onset, deceleration of head growth with acquired microcephaly, movement disorder with ataxia, dystonia, and spasticity) that may suggest GLUT1DS.

Published
2020

6. Type I interferon-mediated autoinflammation due to DNase II deficiency

Author

Flavio Faletra, Gabriele Stocco, Evelyn Hartmann, Chantal Brouzes, Flavia Guillem, Fabrice Porcheray, Florence Uettwiller, Carolina Uggenti, Diego Vozzi, Marion Rabant, Capucine Picard, Nicolas Cagnard, Elisa Piscianz, Olivier Hermine, Andrea Taddio, Sophie Candon, Gunther Hartmann, Leo A. H. Zeef, Pierre Quartier, Marie Alexandra Alyanakian, Brigitte Bader-Meunier, Benoit Beitz, Gillian I. Rice, Muriel Girard, Monique Fabre, Alberto Tommasini, Dominique Lasne, Marine Depp, Nathalie Boddaert, Mathieu P Rodero, Stefano Volpi, Marco Gattorno, Yanick J. Crow, Eva Bartok, Michael Dussiot, Michel Polak, Tiffany Pascreau, Roberta Caorsi, Erika Della Mina, Naoki Kitabayashi, Annalisa Marcuzzi, Vincent Bondet, Paolo Picco, Luis Seabra, Jacques Beltrand, Erica Valencic, Marie-Louise Frémond, Bénédicte Neven, Frédéric Rieux-Laucat, Darragh Duffy, Alessandra Tesser, Patrick Nitschke, Anna Monica Bianco, Marina Charbit, Annie Harroche, Serena Pastore, Winfried Barchet, Laboratory of neurogenetics and neuroinflammation (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), University of Trieste, University of Bonn, Academic Unit of Medical Genetic, University of Manchester [Manchester], Microbiology Technology Institute, BIOASTER Microbiology Technology Institute [Lyon], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Giannina Gaslini Institute, Istituto Giannina Gaslini, Genova, Immunologia Clinica e Sperimentale, Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Radiologie et imagerie médicale [CHU Necker], Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Service de néphrologie pédiatrique [CHU Necker], Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Centre d'étude des Déficits Immunitaires, Service d'endocrinologie, gynécologie et diabétologie pédiatriques [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Life Sciences, Institute of Clinical Chemistry and Pharmacology, Center for Integrated Oncology, University Hospital of Bonn, Service d'Hématologie Adulte, IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy, Y.J.C. acknowledges the European Research Council (GA 309449), and a state subsidymanaged by the National Research Agency (France) under the 'Investments for the Future'program bearing the reference ANR-10-IAHU-01. We thank ImmunoQure AGfor sharing of antibodies used to assess interferon alpha protein levels in the Simoa assay.M.-L.F. is supported by the Institut National de la Santé et de la Recherche Médicale(Grant number 000427993). A.T. and M.G. acknowledge the Italian Telethon (Grant no.GGP15241A). A.T. acknowledges the Institute for Maternal and Child Health-IRCCS'Burlo Garofolo' (RC 17/2014 funded by Italian Ministry of Health, art 12 and 12bis D.lgs 502/92), the 'Associazione Azzurra Malattie Rare'and the 'Beneficientia Stiftung in Vaduz'. We would like to thank Olivier pellet and Jerome Megret from theflow cytometry platform at SFR Necker (INSERM US24-CNRS UMS 3633) for their help withperipheral blood mononuclear cell subset isolation. We would like to thank the Geno-mics Platform, INSERM UMR1163 for whole-exome sequencing. E.B., G.H., and W.B.acknowledge DZIF funding and German Research Foundation (DFG) grants EXC1023:ImmunoSensation, CRCs 670 and 704, ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), 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 du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), BIOASTER, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Università degli studi di Trieste = University of Trieste, Universität Bonn = University of Bonn, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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 Hospital Bonn, Vougny, Marie-Christine, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Definition and characterization of type I interferonopathies - T1-IFN - - EC:FP7:ERC2013-03-01 - 2018-02-28 - 309449 - VALID, Rodero, Mathieu P., Tesser, Alessandra, Bartok, Eva, Rice, Gillian I., Della Mina, Erika, Depp, Marine, Beitz, Benoit, Bondet, Vincent, Cagnard, Nicola, Duffy, Darragh, Dussiot, Michael, Frã©mond, Marie-Louise, Gattorno, Marco, Guillem, Flavia, Kitabayashi, Naoki, Porcheray, Fabrice, Rieux-Laucat, Frederic, Seabra, Lui, Uggenti, Carolina, Volpi, Stefano, Zeef, Leo A. H., Alyanakian, Marie-Alexandra, Beltrand, Jacque, Bianco, Anna Monica, Boddaert, Nathalie, Brouzes, Chantal, Candon, Sophie, Caorsi, Roberta, Charbit, Marina, Fabre, Monique, Faletra, Flavio, Girard, Muriel, Harroche, Annie, Hartmann, Evelyn, Lasne, Dominique, Marcuzzi, Annalisa, Neven, Bã©nã©dicte, Nitschke, Patrick, Pascreau, Tiffany, Pastore, Serena, Picard, Capucine, Picco, Paolo, Piscianz, Elisa, Polak, Michel, Quartier, Pierre, Rabant, Marion, Stocco, Gabriele, Taddio, Andrea, Uettwiller, Florence, Valencic, Erica, Vozzi, Diego, Hartmann, Gunther, Barchet, Winfried, Hermine, Olivier, Bader-Meunier, Brigitte, Tommasini, Alberto, and Crow, Yanick J.

Subjects
Genetics and Molecular Biology (all), Male, 0301 basic medicine, Erythroblasts, [SDV]Life Sciences [q-bio], DNASE2, type I interferon, autoinflammation, exome sequencing, Up-Regulation/drug effects, General Physics and Astronomy, Erythroblasts/immunology, DNASE2, type I interferon, autoinflammation, exome sequencing, Biochemistry, LS3_11, 0302 clinical medicine, Interferon, Interferon-alpha/blood, Membranoproliferative glomerulonephritis, STAT1, Phosphorylation, lcsh:Science, Child, ComputingMilieux_MISCELLANEOUS, Deoxyribonucleases, Multidisciplinary, biology, RNA, Messenger/analysis, Chemistry (all), Endodeoxyribonucleases/deficiency, Up-Regulation, 3. Good health, STAT1 Transcription Factor, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, STAT1 Transcription Factor/metabolism, Antibody, Signal Transduction, medicine.drug, STAT3 Transcription Factor, [SDV.IMM] Life Sciences [q-bio]/Immunology, Adolescent, Science, Alpha interferon, Antiviral Agents/pharmacology, Hematopoiesis/immunology, Antiviral Agents, Article, General Biochemistry, Genetics and Molecular Biology, Deoxyribonucleases/deficiency, NO, Physics and Astronomy (all), 03 medical and health sciences, Downregulation and upregulation, medicine, Humans, RNA, Messenger, Signal Transduction/immunology, Endodeoxyribonucleases, Innate immune system, Sequence Analysis, RNA, Gene Expression Profiling, Hereditary Autoinflammatory Diseases, Interferon-alpha, General Chemistry, medicine.disease, Hematopoiesis, 030104 developmental biology, STAT3 Transcription Factor/metabolism, Hereditary Autoinflammatory Diseases/blood, Mutation, Immunology, biology.protein, Nucleic acid, lcsh:Q, Biochemistry, Genetics and Molecular Biology (all), 030215 immunology
Abstract

Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans., Nucleic acid sensing is important to ensure that an innate immune response is only mounted against microbial nucleic acid. Here, the authors identify loss-of-function mutations in the DNASE2 gene that cause type I interferon-mediated autoinflammation due to enhanced systemic interferon signaling.

Published
2017

7. Molecular cytogenetic characterization of 2p23.2p23.3 deletion in a child with developmental delay, hypotonia and cryptorchism

Author

Flavio Faletra, Paolo Gasparini, Vanna Pecile, Maria Santa Rocca, Raffaella Devescovi, Rocca, Maria Santa, Faletra, Flavio, Devescovi, Raffaella, Gasparini, Paolo, and Pecile, Vanna

Subjects
Male, Muscle Hypotonia, Developmental Disabilitie, Developmental Disabilities, Cryptorchidism, Deletion 2p23, DTNB, SNP array, Child, Preschool, Comparative Genomic Hybridization, Facies, Humans, Infant, Phenotype, Polymorphism, Single Nucleotide, Chromosome Deletion, Chromosomes, Human, Pair 2, Genetics, Genetics (clinical), Biology, Chromosomes, Genetic, medicine, Polymorphism, Dysmorphic facial features, Child, Preschool, Gtg banding, Chromosome, Single Nucleotide, General Medicine, Facie, Hypotonia, Pair 2, Chromosomal region, medicine.symptom, Human, Comparative genomic hybridization
Abstract

Deletions of the short arm of chromosome 2 are exceedingly rare and only nine cases involving regions from 2p23 to 2pter have been reported to date. Most of these deletions had only been analysed by GTG banding. Here, we report an interstitial de novo deletion resulting in a microdeletion of 3.9 Mb involving 2p23.2-p23.3 segment, detected by SNP-array analysis, in a 5 year-old boy showing hypotonia, over- weight, dysmorphic facial features and cryptorchidism. We compared the clinical features of the present case to previously described patients with deletions within this chromosomal region. Our case adds new information to the deletion of the distal part of chromosome 2p improving the knowledge on this rearrangement.

Published
2013

8. Contribution of SNP arrays in diagnosis of deletion 2p11.2–p12

Author

Paolo Gasparini, Antonella Fabretto, Vanna Pecile, Maria Santa Rocca, Aldo Skabar, Flavio Faletra, Ombretta Carlet, Rocca, Maria Santa, Fabretto, Antonella, Faletra, Flavio, Carlet, Ombretta, Skabar, Aldo, Gasparini, Paolo, and Pecile, Vanna

Subjects
LRRTM1, Biology, Polymorphism, Single Nucleotide, Microdeletion 2p11.2-p12, SNP array analysis, Intellectual Disability, Genetics, medicine, SNP array analysi, Humans, SNP, Abnormalities, Multiple, SPG31, Child, Snp array analysis, Gene, Oligonucleotide Array Sequence Analysis, Sequence Deletion, Chromosome, Karyotype, General Medicine, Chromosomes, Human, Pair 2, Speech delay, REEP1, Female, medicine.symptom, Haploinsufficiency
Abstract

Deletions of the short arm of chromosome 2 are exceedingly rare, having been reported in few patients. Fur- thermore most cases with deletion in 2p11.2–p12 have been studied using standard karyotype and so it is not possible to delineate the precise size of deletions. Here, we describe a 9-year-old girl with a 9.4 Mb de novo interstitial deletion of region 2p11.2–p12 identified by SNP array analysis. The deleted region encompasses over 40 known genes, including LRRTM1, CTNNA2 and REEP1, haploinsuffi- ciency of which could explain some clinical features of this patient such as mental retardation, speech delay and gait abnormalities. A comparison of our case with previously reported patients who present deletions in 2p11.2–p12 was carried out. Our case adds new information to the deletion of 2p11.2–p12, improving the knowledge on this rearrangement.

Published
2012

9. A new case of duplication of the MDS region identified by high-density SNP arrays and a review of the literature

Author

Antonella Fabretto, Vanna Pecile, Paolo Gasparini, Flavio Faletra, Marco Carrozzi, Raffaella Devescovi, Faletra, Flavio, Devescovi, Raffaella, Pecile, Vanna, Fabretto, Antonella, Carrozzi, Marco, and Gasparini, Paolo

Subjects
Lissencephaly, Locus (genetics), Pervasive Developmental Disorder, Biology, Polymorphism, Single Nucleotide, PAFAH1B1, Autistic Spectrum Disorder, Gene Duplication, Gene duplication, Genetics, medicine, Humans, SNP, Child, Gene, YWHAE, Oligonucleotide Array Sequence Analysis, Single Nucleotide Polymorphism Array, Single Nucleotide Polymorphism Marker, General Medicine, Prognosis, medicine.disease, Human genetics, Autistic Spectrum Disorder, Single Nucleotide Polymorphism Marker, Pervasive Developmental Disorder, Single Nucleotide Polymorphism Array, Lissencephaly, Myelodysplastic Syndromes, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Female, Microtubule-Associated Proteins
Abstract

The deletion of the locus 17p13 was associated with Miller–Dieker lissencephaly syndrome (MDLS). Deletion (Delatycki and Leventer 2009) or mutations (Lo Nigro et al. 1997) in the PAFAH1B1 (601545) gene cause lissencephaly (Gu and Lupski 2008), but facial dysmorphology and other abnormalities in patients with MDLS seem to be the result of the deletion of additional genes distal to PAFAH1B1 (Cardoso et al. 2003; Saillour et al. 2009). The gene responsible for the greater severity of MDLS compared to isolated lissencephaly is the YWHAE (Haverfield et al. 2009) (605066) gene, encoding 14-3-3-epsilon. It was very recently demonstrated that the duplication in 17p13 is a new clinical entity (OMIM 613215), characterized by mental retardation and other variable clinical and radiological findings (Roos et al. 2009; Spalice et al. 2009). There are three different areas within the MDS region containing dosage-sensitive genes. One containing the PAFAH1B1 gene and the other, more distal, which includes the TUSC5, YWHAE, CRK, and MYO1C genes. Until now, few cases have been described with duplication in the MDS region (Mei et al. 2008; Bi et al. 2009) and only two of them show a duplication including only the PAFAH1B1 area. All patients with duplication in the MDS region have common clinical and phenotypic features. Nevertheless, there are several important differences between those with only duplication in the PAFAH1B1 area as compared with those who have also (or only) a duplication in the distal area. Clinical report

Published
2010

10. Altered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype

Author

Silvia Giliani, Vassilios Lougaris, Anna Monica Bianco, Antonino Trizzino, Annalisa Marcuzzi, Fabio Facchetti, Daniele Moratto, Anders Fasth, Filippo Salvini, Erica Valencic, Manuela Baronio, Martina Girardelli, Alessandro Plebani, Elisa Piscianz, Gaetana Lanzi, Flavio Faletra, Alberto Tommasini, Diego Vozzi, Claudia Loganes, Lougaris, Vassilio, Faletra, Flavio, Lanzi, Gaetana, Vozzi, Diego, Marcuzzi, Annalisa, Valencic, Erica, Piscianz, Elisa, Bianco, ANNA MONICA ROSARIA, Girardelli, Martina, Baronio, Manuela, Loganes, Claudia, Fasth, Ander, Salvini, Filippo, Trizzino, Antonino, Moratto, Daniele, Facchetti, Fabio, Giliani, Silvia, Plebani, Alessandro, and Tommasini, Alberto

Subjects
Male, Hyper IgM syndrome, Hyper-IgM Immunodeficiency Syndrome, Immunology, Germinal Center (GC) reaction, Biology, medicine.disease_cause, NO, B cells, Hyper-IgM syndrome, PIK3R1, B-Lymphocytes, Child, Preschool, Female, Germinal Center, Humans, Infant, Mutation, Phenotype, Phosphatidylinositol 3-Kinases, RNA Splice Sites, Sequence Analysis, DNA, Immunology and Allergy, Child, Preschool, Sequence Analysis, DNA, medicine, B cell, B-Lymphocyte, Germinal center, medicine.disease, Peripheral, Class Ia Phosphatidylinositol 3-Kinase, medicine.anatomical_structure, RNA Splice Site, Phosphatidylinositol 3-Kinase, Human
Published
2015

11. Two‑gene mutation in a single patient: Biochemical and functional analysis for a correct interpretation of exome results

Author

Annalisa Marcuzzi, Alessandra Knowles, Martina Girardelli, Alberto Tommasini, Flavio Faletra, Giorgio Zauli, Diego Vozzi, Anna Monica Bianco, Bianco, ANNA MONICA ROSARIA, Faletra, Flavio, Vozzi, Diego, Girardelli, Martina, Knowles, A, Tommasini, Alberto, Zauli, Giorgio, and Marcuzzi, Annalisa

Subjects
Male, Cancer Research, Gene mutation, Genotype-phenotype, Mevalonate, Mevalonate kinase deficiency, RAB40AL, Rare disease, Biochemistry, Genetics, Molecular Biology, Molecular Medicine, Oncology, Bioinformatics, medicine.disease_cause, mevalonate, X Chromosome Inactivation, Genotype, Databases, Genetic, Missense mutation, Exome, Child, Exome sequencing, Mutation, High-Throughput Nucleotide Sequencing, Genetic Diseases, X-Linked, Phosphotransferases (Alcohol Group Acceptor), Phenotype, Receptors, Androgen, Female, Genetic Markers, Hearing Loss, Sensorineural, Mutation, Missense, rare disease, Mevalonic Acid, Mothers, Biology, NO, Mitochondrial Proteins, Intellectual Disability, Genetic variation, medicine, Humans, Abnormalities, Multiple, Genetic Association Studies, Genetic Variation, medicine.disease, genotype‑phenotype, ras Proteins, mevalonate, rare disease, RAB40AL, mevalonate kinase deficiency, genotype‑phenotype, Mevalonate Kinase Deficiency
Abstract

Next-generation sequencing (NGS) has generated a large amount of sequence data with the requirement of frequent critical revisions of reported mutations. This innovative tool has proved to be effective in detecting pathogenic mutations; however, it requires a certain degree of experience to identify incidental findings. In the present study, whole exome sequencing analysis was performed for the molecular diagnosis and correct genotype/phenotype correlation between parents and a patient presenting with an atypical phenotype. In addition, mevalonic acid quantification and frequency analysis of detected variants in public databases and X‑chromosome inactivation (XCI) studies on the patient's mother were performed. V377I as well as the S135L mutations were identified on the mevalonate kinase deficiency gene and the levels of mevalonic acid in the patient were 5,496 µg/ml. A D59G variation, reported in ESP6500 in two healthy individuals, was found on the Martin Probst syndrome gene (RAB40AL). Based on XCI studies on the patient's mother, it is likely that RAB40AL escapes XCI, while still remaining balanced. In conclusion, the results of the present study indicated that the Martin Probst syndrome is an X‑linked condition, which is probably not caused by RAB40AL mutations. Although NGS is a powerful tool to identify pathogenic mutations, the analysis of genetic data requires expert critical revision of all detected variants.

Published
2014

12. PMM2-CDG: Phenotype and genotype in four affected family members

Author

Flavio Faletra, Eleonora De Martino, Stefania Biffi, Giovanni Maria Severini, Barbara Bortot, Dora Cosentini, Marco Carrozzi, Bortot, Barbara, Cosentini, Dora, Faletra, Flavio, Biffi, Stefania, DE MARTINO, Eleonora, Carrozzi, Marco, and Severini, Giovanni Maria

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Glycosylation, Genotype, Phenotype-genotype correlation, DNA Mutational Analysis, N-glycosylation, Genetic Association Studie, Biology, Compound heterozygosity, medicine.disease_cause, PMM2-CDG, DNA Mutational Analysi, chemistry.chemical_compound, Congenital Disorders of Glycosylation, N-linked glycosylation, medicine, Genetics, Humans, Preschool, Child, Gene, Genetic Association Studies, Aged, Mutation, General Medicine, Middle Aged, Phenotype, Pedigree, ALG6, Child, Preschool, Female, Phosphotransferases (Phosphomutases), chemistry, Lipid glycosylation, Human
Abstract

Congenital disorders of glycosylation (CDG) are genetic defects in protein and lipid glycosylation. PMM2-CDG is the most prevalent protein N-glycosylation disorder with more than 700 reported patients. Here we report on a large Italian family with four affected members and three mutations. Two young sisters are compound heterozygous for mutations p.Leu32Arg and p.Arg141His, while two paternal great-aunts are compound heterozygosity for p.Leu32Arg and p.Thr237Met. The latter association has not been reported before. The most severely affected member had in addition an ALG6 mutation known to exacerbate the phenotype of patients with PMM2-CDG. Abbreviations CDG, Congenital disorders of glycosylation; PMM2, phosphomannomutase 2; ALG6, alpha-1,3-glucosyltransferase; CDT, carbohydrate-deficient transferrin

Published
2013

13. Horizontal gaze palsy and progressive scoliosis without ROBO3 mutations

Author

Paolo Gasparini, Stefano Pensiero, Flavio Faletra, Thomas M. Bosley, Ibrahim A. Alorainy, Khaled K. Abu-Amero, Fulvio Parentin, Dario Catalano, Ali Hellani, Abu-Amero, Khaled K., Faletra, Flavio, Gasparini, Paolo, Parentin, Fulvio, Pensiero, Stefano, Alorainy, Ibrahim A., Hellani, Ali M., Catalano, Dario, and Bosley, Thomas M.

Subjects
Male, horizontal gaze palsy and progressive scoliosis, Decussation, Proband, Pathology, medicine.medical_specialty, ROBO3 gene, Receptors, Cell Surface, Scoliosis, scoliosis, Ophthalmology, Pediatrics, Perinatology and Child Health, Genetics (clinical), Biology, Pediatrics, Ocular Motility Disorders, Pathognomonic, Oculomotor Nerve Diseases, medicine, Humans, Kyphosis, Receptors, Immunologic, Child, scoliosi, Chromosomal Deletion, horizontal gaze palsy and progressive scoliosi, Facial weakness, Horizontal gaze palsy, Perinatology and Child Health, medicine.disease, Magnetic Resonance Imaging, Pedigree, Mutation, medicine.symptom, Horizontal pendular nystagmus
Abstract

Background: To describe clinical and genetic observations in a patient with horizontal gaze palsy and progressive scoliosis (HGPPS) without identified mutations in the ROBO3 gene. Materials and Methods: Neurologic and orthopedic evaluation of the proband; sequencing all exons, exon-intron boundaries, and promoter region of ROBO3 in the proband and his mother. Array CGH was also carried out in the proband and his mother to evaluate possible chromosomal deletion(s) and/or duplication(s). Results: The proband had complete horizontal gaze restriction with full vertical gaze and small amplitude horizontal pendular nystagmus. He also had severe scoliosis and brainstem hypoplasia pathognomonic of HGPPS. However, complete sequencing of ROBO3 twice in both forward and reverse directions did not reveal any mutations. Array CGH investigation revealed no chromosomal abnormalities. Conclusions: This patient had clinical and neuroimaging characteristics considered pathognomonic of HGPPS and yet did not have ROBO3 mutations. A clinical misdiagnosis is unlikely in the absence of facial weakness (typical of Moebius syndrome), deafness (typical of the HOXA1 spectrum), or mental retardation (typical of other central decussation abnormalities). It is perhaps more likely that a phenotype identical to HGPPS can be caused by abnormalities in ROBO3 splice variant expression, by mutations of a gene other than ROBO3, or by some environmental or epigenetic factor(s) inhibiting the action of ROBO3 or its protein product in the developing brainstem.

Published
2011

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