Contributors: Institut de la Vision; Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); CHU Trousseau APHP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU); IntegraGen SA; Génétique et Physiologie de l'Audition; Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur Paris (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM); Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO); Sorbonne Université (SU); Eberhard Karls Universität Tübingen = University of Tübingen; Centre de référence des Surdités Génétiques CHU Necker, Paris; Hôpital Necker - Enfants Malades AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); University of Naples Federico II = Università degli studi di Napoli Federico II; Telethon Institute of Genetics and Medicine = Istituto Telethon di Genetica e Medicina (TIGEM); Seconda Università degli Studi di Napoli = Second University of Naples; University Medical Centre Ljubljana Ljubljana, Slovenia (UMCL); University of Ljubljana; Hospital Sant Joan de Déu Barcelona; Kennedy Center; Collège de France - Chaire Génétique et physiologie cellulaire; Collège de France (CdF (institution)); This work was supported by the European Union Seventh Framework Programme under the grant agreement HEALTH-F2-2010-242013 (TREATRUSH), ANR-15-RHUS-001 (LIGHT4DEAF), LHW-Stiftung, Fondation Raymonde & Guy Strittmatter, FAUN Stiftung, Conny Maeva Charitable Foundation, Fondation Orange, Fondation BNP Paribas, LABEX Lifesenses ANR-10-LABX-65 , 'the Foundation Fighting Blindness Paris Center Grant', and the Slovenian research agency (ARRS P3-0333).; We are grateful to the patients and their families for their participation in the study. DNA samples included in this study originated from the NeuroSensCol** DNA bank, part of the BioCollections network for research in neuroscience (PI: JA Sahel, co-PI: I Audo, in partnership with the CHNO des Quinze-Vingts, Inserm and the CNRS), and the Tuebingen RetDis biobank (PI: B Wissinger, co-PI S Kohl).; ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015); ANR-10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE(2010); European Project: 242013,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,TREATRUSH(2010)
نبذة مختصرة : International audience ; Usher syndrome (USH), the most prevalent cause of hereditary deafness-blindness, is an autosomal recessive and genetically heterogeneous disorder. Three clinical subtypes (USH1-3) are distinguishable based on the severity of the sensorineural hearing impairment, the presence or absence of vestibular dysfunction, and the age of onset of the retinitis pigmentosa. A total of 10 causal genes, 6 for USH1, 3 for USH2, and 1 for USH3, and an USH2 modifier gene, have been identified. A robust molecular diagnosis is required not only to improve genetic counseling, but also to advance gene therapy in USH patients. Here, we present an improved diagnostic strategy that is both cost- and time-effective. It relies on the sequential use of three different techniques to analyze selected genomic regions: targeted exome sequencing, comparative genome hybridization, and quantitative exon amplification. We screened a large cohort of 427 patients (139 USH1, 282 USH2, and six of undefined clinical subtype) from various European medical centers for mutations in all USH genes and the modifier gene. We identified a total of 421 different sequence variants predicted to be pathogenic, about half of which had not been previously reported. Remarkably, we detected large genomic rearrangements, most of which were novel and unique, in 9% of the patients. Thus, our strategy led to the identification of biallelic and monoallelic mutations in 92.7% and 5.8% of the USH patients, respectively. With an overall 98.5% mutation characterization rate, the diagnosis efficiency was substantially improved compared with previously reported methods.
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