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Aicardi-Goutières syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3′→5′ exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P = .001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified. © 2007 by The American Society of Human Genetics. All rights reserved.
Leeds Institute of Molecular Medicine, Leeds
DNA Laboratory Department of Clinical Genetics St. James's University Hospital, Leeds
Cancer Research UK Mutation Detection Facility, Leeds
Department of Paediatric Neurology Leeds General Infirmary, Leeds
Department of Paediatric Neurology Erasme Hospital, Brussels
Children's Hospital Queen Fabiola, Brussels
Service de Neuropédiatrie Hôpital Trousseau
Department of Paediatric Neurology Hôpital Trousseau
Pediatric Neurology Department Hôpital Bicêtre
Institut de Myologie Groupe Hospitalier Pitié-Salpêtrière
Service de Virologie Hôpital Cochin-St. Vincent de Paul, Paris
Department of Clinical Biochemistry Hospital Sant Joan de Déu-Ciberer, Barcelona
Department of Barcelona Pediatric Neurology Hospital Sant Joan de Déu-Ciberer, Barcelona
Department of Paediatrics St. Luke's Hospital, Guardamangia
Department of Molecular and Human Genetics Baylor College of Medicine, Houston
Serive de Neurologie Centre Hospitalier, Pau
Department of Paediatrics Children's Hospital, Sheffield
Developmental and Metabolic Neurology Branch National Institute of Neurological Disorders and Stroke National Institutes of Health, Bethesda
Department of Human Genetics Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen
Unit of Molecular Medicine Bambino Gesù Children's Research Hospital, Rome
Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Casa Sollievo Della Sofferenza Mendel Institute, Rome
Muscular and Neurodegenerative Disease Unit G. Gaslini Institute, Genova
Department of Clinical Genetics Churchill Hospital, Oxford
Division of Clinical Chemistry and Biochemistry University Children's Hospital, Zurich
Clinical Genetics Unit Birmingham Women's Hospital, Birmingham
Department of Paediatrics Sandwell and West Birmingham NHS Trust, Birmingham
Neurology Department Birmingham Children's Hospital, Birmingham
Department of Human Genetics Radboud University, Nijmegen
Department of Pediatric Neurology Radboud University, Nijmegen
Department of Paediatric Neurology Royal Children's Hospital, Brisbane, QLD
Genetic Health Queensland Royal Children's Hospital, Brisbane, QLD
Serviço de Aconselhamento Genético Universidade Estadual de São Paulo, Botucatu
Academic Unit of Medical Genetics St. Mary's Hospital, Manchester
Kinderkrankenhaus Auf der Bult, Hannover
Department of Paediatrics Bradford National Health Service (NHS) Trust, Bradford
Developmental Neurology Department Fondazione Istituto Neurologico C. Besta, Milan
Grampian Clinical Genetics Centre, Aberdeen
Department of Neonatology University Hospital, Ghent
Department of Pediatrics University Hospital, Ghent
Department of Clinical Genetics Maastricht University Hospital, Maastricht
Department of Neurology Maastricht University Hospital, Maastricht
Department of Paediatrics and Imaging Sciences Imperial College Great Ormond Street Hospital, London
St. Mary's NHS Trust Great Ormond Street Hospital, London
Department of Ophthalmology Great Ormond Street Hospital, London
North East Thames Regional Genetics Service Great Ormond Street Hospital, London
Evelina Children's Hospital Guy's and St. Thomas' NHS Trust, London
Department of Paediatrics Université Laval Medical School, Québec
Clinical Genetics Unit Hospital de Cruces, Baracaldo
Service de Génétique Médicale Centre Hospitalier Universitaire Pellegrin Enfants, Bordeaux
Unité de Neurologie de l'Enfant et de l'Adolescent Centre Hospitalier Universitaire Pellegrin Enfants, Bordeaux
National Centre for Medical Genetics Our Lady's Hospital, Dublin
Department of Paediatric Neurology Children's University Hospital, Dublin
Department of Medical Genetics Rikshospitalet-Radiumhospitalet, Oslo
Department of Paediatrics Rikshospitalet-Radiumhospitalet, Oslo
Rikshospitalet-Radiumhospitalet, Oslo
Department of Pediatrics Academic Medical Center, Amsterdam
Department of Child Neurology Vrije Universiteit Medical Center, Amsterdam
Medical Research Council Human Genetics Unit Western General Hospital, Edinburgh
Department of Clinical Genetics Leiden University Medical Center, Leiden
Division of Pediatric Neurology Oregon Health and Science University, Portland, OR
Pediatric Neurology Klinikum Aschaffenburg, Aschaffenburg
Department of Neurology Royal Children's Hospital, Parkville, Vic.
Division of Clinical Genetics Department for Medical Genetics Medical University Innsbruck, Innsbruck
Department of Pediatrics Division of Pediatric Neurology and Inborn Errors of Metabolism Children's Hospital Innsbruck, Innsbruck
Klinik für Kinder und Jugendliche, Konstanz
Paediatric Neurology University Hospitals of Gasthuisberg, Leuven
Department of Child Neurology and Psychiatry IRCCS Casimiro Mondino Institute of Neurology, Pavia
Department of Neurogenetics School of Medicine of Ribeirao Preto, Ribeirao Preto
Greenwood Genetic Center, Greenwood, SC
Raphael Recanati Genetic Institute Rabin Medical Center, Petach-Tikva
Department of Paediatrics Crosshouse Hospital, Ayr
Fraser of Allander Neurosciences Unit Royal Hospital for Sick Children, Glasgow
Duncan Guthrie Institute of Medical Genetics Royal Hospital for Sick Children, Glasgow
Division of Medical Genetics Montreal Children's Hospital, Montreal
Department of Paediatric Neurology University Hospitals of Leicester NHS Trust, Leicester
University Hospital of Aarhus, Aarhus
Division of Pediatric Dermatology British Columbia's Children's Hospital, Vancouver, BC
Institut de Pathologie et de Génétique, Gosselies
Pediatric Neurology Department Guide Chauliac Hospital, Montpellier
Servicio de Pediatría Hospital Universitario Doctor Peset, Valencia
Genetic Institute Ha'Emek Medical Center, Afula
Rappaport Faculty of Medicine Technion, Haifa
Neuropediatrics Unit Complejo Hospitalario de Jean, Jean
Department of Paediatrics Manor Hospital, Walsall
Division of Neuropediatrics University Hospital, Freiburg
Genetic Health Services Victoria Royal Children's Hospital, Vic.
Service de Génétique Hôpital Debrousse, Lyon
Lancashire Teaching Hospitals Trust, Preston
Neonatal Intensive Care Unit Arcispedale Santa Maria Nuova, Reggio Emilia
Center for Medical Genetics, Antwerp
Department of Neurology Children's National Medical Center, Washington, DC
Department of Neuropediatrics Humboldt University, Berlin
Leeds Institute of Molecular Medicine St. James's University Hospital Wellcome Trust Brenner Building, Leeds LS9 7TF
Serviço de Aconselhamento Genético Universidade Estadual de São Paulo, Botucatu
