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Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings.
Schmidt, Axel; Danyel, Magdalena; Grundmann, Kathrin; Brunet, Theresa; Klinkhammer, Hannah; Hsieh, Tzung-Chien; Engels, Hartmut; Peters, Sophia; Knaus, Alexej; Moosa, Shahida; Averdunk, Luisa; Boschann, Felix; Sczakiel, Henrike Lisa; Schwartzmann, Sarina; Mensah, Martin Atta; Pantel, Jean Tori; Holtgrewe, Manuel; Bösch, Annemarie; Weiß, Claudia; Weinhold, Natalie; Suter, Aude-Annick; Stoltenburg, Corinna; Neugebauer, Julia; Kallinich, Tillmann; Kaindl, Angela M; Holzhauer, Susanne; Bührer, Christoph; Bufler, Philip; Kornak, Uwe; Ott, Claus-Eric; Schülke, Markus; Nguyen, Hoa Huu Phuc; Hoffjan, Sabine; Grasemann, Corinna; Rothoeft, Tobias; Brinkmann, Folke; Matar, Nora; Sivalingam, Sugirthan; Perne, Claudia; Mangold, Elisabeth; Kreiss, Martina; Cremer, Kirsten; Betz, Regina C; Mücke, Martin; Grigull, Lorenz; Klockgether, Thomas; Spier, Isabel; Heimbach, André; Bender, Tim; Brand, Fabian.
Afiliación
  • Schmidt A; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
  • Danyel M; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Grundmann K; BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Brunet T; Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
  • Klinkhammer H; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.
  • Hsieh TC; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
  • Engels H; Institut für Medizinische Biometrie, Informatik und Epidemiologie, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
  • Peters S; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
  • Knaus A; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
  • Moosa S; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
  • Averdunk L; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
  • Boschann F; Institute for Medical Genetics, Stellenbosch University, Cape Town, South Africa.
  • Sczakiel HL; Department of Pediatrics, University Hospital Düsseldorf, Düsseldorf, Germany.
  • Schwartzmann S; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Mensah MA; BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Pantel JT; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Holtgrewe M; BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Bösch A; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Weiß C; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Weinhold N; BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Suter AA; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Stoltenburg C; Institute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany.
  • Neugebauer J; Core Uni Bioinformatics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Kallinich T; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Kaindl AM; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Holzhauer S; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Bührer C; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Bufler P; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Kornak U; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Ott CE; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Schülke M; Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Nguyen HHP; Center for Chronically Sick Children, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Hoffjan S; Institute of Cell and Neurobiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Grasemann C; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Rothoeft T; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Brinkmann F; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Matar N; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Sivalingam S; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Perne C; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Mangold E; Department of Human Genetics, Ruhr University Bochum, Bochum, Germany.
  • Kreiss M; Department of Human Genetics, Ruhr University Bochum, Bochum, Germany.
  • Cremer K; Department of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany.
  • Betz RC; Department of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany.
  • Mücke M; Department of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany.
  • Grigull L; Department of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany.
  • Klockgether T; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
  • Spier I; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
  • Heimbach A; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
  • Bender T; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
  • Brand F; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Nat Genet ; 56(8): 1644-1653, 2024 Aug.
Article en En | MEDLINE | ID: mdl-39039281
ABSTRACT
Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 150,000. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fenotipo / Secuenciación de Nucleótidos de Alto Rendimiento Límite: Adolescent / Adult / Child / Child, preschool / Female / Humans / Infant / Male País/Región como asunto: Europa Idioma: En Revista: Nat Genet Asunto de la revista: GENETICA MEDICA Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fenotipo / Secuenciación de Nucleótidos de Alto Rendimiento Límite: Adolescent / Adult / Child / Child, preschool / Female / Humans / Infant / Male País/Región como asunto: Europa Idioma: En Revista: Nat Genet Asunto de la revista: GENETICA MEDICA Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos