Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings

Research output: Contribution to journalResearch articleContributed

Contributors

  • Axel Schmidt - , University of Bonn Medical Center (Author)
  • Magdalena Danyel - , Berlin Institute of Health at Charité (Author)
  • Kathrin Grundmann - , University of Tübingen (Author)
  • Theresa Brunet - , Technical University of Munich (Author)
  • Hannah Klinkhammer - , University of Bonn Medical Center (Author)
  • Tzung-Chien Hsieh - , University of Bonn Medical Center (Author)
  • Hartmut Engels - , University of Bonn Medical Center (Author)
  • Sophia Peters - , University of Bonn Medical Center (Author)
  • Alexej Knaus - , University of Bonn Medical Center (Author)
  • Shahida Moosa - , University of Stellenbosch (Author)
  • Luisa Averdunk - , University Hospital Duesseldorf (Author)
  • Felix Boschann - , Berlin Institute of Health at Charité (Author)
  • Henrike Lisa Sczakiel - , Berlin Institute of Health at Charité (Author)
  • Sarina Schwartzmann - , Charité – Universitätsmedizin Berlin (Author)
  • Martin Atta Mensah - , Berlin Institute of Health at Charité (Author)
  • Jean Tori Pantel - , University Hospital Aachen (Author)
  • Manuel Holtgrewe - , Berlin Institute of Health at Charité (Author)
  • Annemarie Bösch - , Charité – Universitätsmedizin Berlin (Author)
  • Claudia Weiß - , Charité – Universitätsmedizin Berlin (Author)
  • Natalie Weinhold - , Charité – Universitätsmedizin Berlin (Author)
  • Aude-Annick Suter - , Charité – Universitätsmedizin Berlin (Author)
  • Corinna Stoltenburg - , Charité – Universitätsmedizin Berlin (Author)
  • Julia Neugebauer - , Charité – Universitätsmedizin Berlin (Author)
  • Tillmann Kallinich - , Charité – Universitätsmedizin Berlin (Author)
  • Angela M Kaindl - , Charité – Universitätsmedizin Berlin (Author)
  • Susanne Holzhauer - , Charité – Universitätsmedizin Berlin (Author)
  • Christoph Bührer - , Charité – Universitätsmedizin Berlin (Author)
  • Philip Bufler - , Charité – Universitätsmedizin Berlin (Author)
  • Uwe Kornak - , Charité – Universitätsmedizin Berlin (Author)
  • Claus-Eric Ott - , Charité – Universitätsmedizin Berlin (Author)
  • Markus Schülke - , Charité – Universitätsmedizin Berlin (Author)
  • Hoa Huu Phuc Nguyen - , Ruhr University Bochum (Author)
  • Sabine Hoffjan - , Ruhr University Bochum (Author)
  • Corinna Grasemann - , Ruhr University Bochum (Author)
  • Tobias Rothoeft - , Ruhr University Bochum (Author)
  • Folke Brinkmann - , Ruhr University Bochum (Author)
  • Nora Matar - , Ruhr University Bochum (Author)
  • Sugirthan Sivalingam - , University of Bonn Medical Center (Author)
  • Claudia Perne - , University of Bonn Medical Center (Author)
  • Elisabeth Mangold - , University of Bonn Medical Center (Author)
  • Martina Kreiss - , University of Bonn Medical Center (Author)
  • Kirsten Cremer - , University of Bonn Medical Center (Author)
  • Regina C Betz - , University of Bonn Medical Center (Author)
  • Martin Mücke - , University of Bonn Medical Center (Author)
  • Lorenz Grigull - , University of Bonn Medical Center (Author)
  • Thomas Klockgether - , University of Bonn Medical Center (Author)
  • Isabel Spier - , University of Bonn Medical Center (Author)
  • André Heimbach - , University of Bonn Medical Center (Author)
  • Tim Bender - , University of Bonn Medical Center (Author)
  • Fabian Brand - , University of Bonn Medical Center (Author)
  • Christiane Stieber - , University of Bonn Medical Center (Author)
  • Alexandra Marzena Morawiec - , University of Bonn Medical Center (Author)
  • Pantelis Karakostas - , University of Bonn Medical Center (Author)
  • Valentin S Schäfer - , University of Bonn Medical Center (Author)
  • Sarah Bernsen - , University of Bonn Medical Center (Author)
  • Patrick Weydt - , University of Bonn Medical Center (Author)
  • Sergio Castro-Gomez - , University of Bonn Medical Center (Author)
  • Ahmad Aziz - , University of Bonn Medical Center (Author)
  • Marcus Grobe-Einsler - , University of Bonn Medical Center (Author)
  • Okka Kimmich - , University of Bonn Medical Center (Author)
  • Xenia Kobeleva - , University of Bonn Medical Center (Author)
  • Demet Önder - , University of Bonn Medical Center (Author)
  • Hellen Lesmann - , University of Bonn Medical Center (Author)
  • Sheetal Kumar - , University of Bonn Medical Center (Author)
  • Pawel Tacik - , University of Bonn Medical Center (Author)
  • Meghna Ahuja Basin - , University of Bonn Medical Center (Author)
  • Pietro Incardona - , University of Bonn Medical Center (Author)
  • Min Ae Lee-Kirsch - , Department of Paediatrics, University Center for Rare Diseases, University Hospital Carl Gustav Carus Dresden (Author)
  • Reinhard Berner - , Department of Paediatrics, University Center for Rare Diseases, University Hospital Carl Gustav Carus Dresden (Author)
  • Catharina Schuetz - , Department of Paediatrics, University Center for Rare Diseases, University Hospital Carl Gustav Carus Dresden (Author)
  • Julia Körholz - , Department of Paediatrics, University Center for Rare Diseases, University Hospital Carl Gustav Carus Dresden (Author)
  • Tanita Kretschmer - , Department of Paediatrics, University Center for Rare Diseases, University Hospital Carl Gustav Carus Dresden (Author)
  • Nataliya Di Donato - , Institute of Clinical Genetics, University Center for Rare Diseases (Author)
  • Evelin Schröck - , Institute of Clinical Genetics, University Center for Rare Diseases (Author)
  • André Heinen - , Department of Paediatrics, University Center for Rare Diseases, University Hospital Carl Gustav Carus Dresden (Author)
  • Ulrike Reuner - , Department of Neurology, University Center for Rare Diseases (Author)
  • Amalia-Mihaela Hanßke - , University Center for Rare Diseases (Author)
  • Frank J Kaiser - , University Hospital Essen (Author)
  • Eva Manka - , University Hospital Essen (Author)
  • Martin Munteanu - , University Hospital Essen (Author)
  • Alma Kuechler - , University Hospital Essen (Author)
  • Kiewert Cordula - , University Hospital Essen (Author)
  • Raphael Hirtz - , University Hospital Essen (Author)
  • Elena Schlapakow - , Martin Luther University Hospital (Author)
  • Christian Schlein - , University Hospital Hamburg Eppendorf (Author)
  • Jasmin Lisfeld - , University Hospital Hamburg Eppendorf (Author)
  • Christian Kubisch - , University Hospital Hamburg Eppendorf (Author)
  • Theresia Herget - , University Hospital Hamburg Eppendorf (Author)
  • Maja Hempel - , Heidelberg University  (Author)
  • Christina Weiler-Normann - , University Hospital Hamburg Eppendorf (Author)
  • Kurt Ullrich - , University Hospital Hamburg Eppendorf (Author)
  • Christoph Schramm - , University Hospital Hamburg Eppendorf (Author)
  • Cornelia Rudolph - , University Hospital Hamburg Eppendorf (Author)
  • Franziska Rillig - , University Hospital Hamburg Eppendorf (Author)
  • Maximilian Groffmann - , University Hospital Hamburg Eppendorf (Author)
  • Ania Muntau - , University Hospital Hamburg Eppendorf (Author)
  • Alexandra Tibelius - , Heidelberg University  (Author)
  • Eva M C Schwaibold - , Heidelberg University  (Author)
  • Christian P Schaaf - , Heidelberg University  (Author)
  • Michal Zawada - , Heidelberg University  (Author)
  • Lilian Kaufmann - , Heidelberg University  (Author)
  • Katrin Hinderhofer - , Heidelberg University  (Author)
  • Pamela M Okun - , University Hospital Heidelberg (Author)
  • Urania Kotzaeridou - , University Hospital Heidelberg (Author)
  • Georg F Hoffmann - , University Hospital Heidelberg (Author)
  • Daniela Choukair - , University Hospital Heidelberg (Author)
  • Markus Bettendorf - , University Hospital Heidelberg (Author)
  • Malte Spielmann - , Universitätsklinikum Schleswig-Holstein - Campus Lübeck (Author)
  • Annekatrin Ripke - , Universitätsklinikum Schleswig-Holstein - Campus Lübeck (Author)
  • Martje Pauly - , Universitätsklinikum Schleswig-Holstein - Campus Lübeck (Author)
  • Alexander Münchau - , University of Lübeck (Author)
  • Katja Lohmann - , University of Lübeck (Author)
  • Irina Hüning - , Universitätsklinikum Schleswig-Holstein - Campus Lübeck (Author)
  • Britta Hanker - , University of Lübeck (Author)
  • Tobias Bäumer - , University of Lübeck (Author)
  • Rebecca Herzog - , Universitätsklinikum Schleswig-Holstein - Campus Lübeck (Author)
  • Yorck Hellenbroich - , Universitätsklinikum Schleswig-Holstein - Campus Lübeck (Author)
  • Dominik S Westphal - , Technical University of Munich (Author)
  • Tim Strom - , Technical University of Munich (Author)
  • Reka Kovacs - , Technical University of Munich (Author)
  • Korbinian M Riedhammer - , Technical University of Munich (Author)
  • Katharina Mayerhanser - , Technical University of Munich (Author)
  • Elisabeth Graf - , Technical University of Munich (Author)
  • Melanie Brugger - , Technical University of Munich (Author)
  • Julia Hoefele - , Technical University of Munich (Author)
  • Konrad Oexle - , Institute of Neurogenomics, Helmholtz Zentrum München, München, Germany. (Author)
  • Nazanin Mirza-Schreiber - , Institute of Neurogenomics, Helmholtz Zentrum München, München, Germany. (Author)
  • Riccardo Berutti - , Institute of Neurogenomics, Helmholtz Zentrum München, München, Germany. (Author)
  • Ulrich Schatz - , Technical University of Munich (Author)
  • Martin Krenn - , Medical University of Vienna (Author)
  • Christine Makowski - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Heike Weigand - , Dr. von Haunersches Kinderspital, München (Author)
  • Sebastian Schröder - , Dr. von Haunersches Kinderspital, München (Author)
  • Meino Rohlfs - , Dr. von Haunersches Kinderspital, München (Author)
  • Katharina Vill - , Dr. von Haunersches Kinderspital, München (Author)
  • Fabian Hauck - , Dr. von Haunersches Kinderspital, München (Author)
  • Ingo Borggraefe - , Dr. von Haunersches Kinderspital, München (Author)
  • Wolfgang Müller-Felber - , Dr. von Haunersches Kinderspital, München (Author)
  • Ingo Kurth - , University Hospital Aachen (Author)
  • Miriam Elbracht - , University Hospital Aachen (Author)
  • Cordula Knopp - , University Hospital Aachen (Author)
  • Matthias Begemann - , University Hospital Aachen (Author)
  • Florian Kraft - , University Hospital Aachen (Author)
  • Johannes R Lemke - , University Hospital Leipzig (Author)
  • Julia Hentschel - , University Hospital Leipzig (Author)
  • Konrad Platzer - , University Hospital Leipzig (Author)
  • Vincent Strehlow - , University Hospital Leipzig (Author)
  • Rami Abou Jamra - , University Hospital Leipzig (Author)
  • Martin Kehrer - , University of Tübingen (Author)
  • German Demidov - , University of Tübingen (Author)
  • Stefanie Beck-Wödl - , University of Tübingen (Author)
  • Holm Graessner - , University of Tübingen (Author)
  • Marc Sturm - , University of Tübingen (Author)
  • Lena Zeltner - , University of Tübingen (Author)
  • Ludger J Schöls - , University Hospital Tübingen (Author)
  • Janine Magg - , University of Tübingen (Author)
  • Andrea Bevot - , University of Tübingen (Author)
  • Christiane Kehrer - , University of Tübingen (Author)
  • Nadja Kaiser - , University of Tübingen (Author)
  • Ernest Turro - , Icahn School of Medicine at Mount Sinai (Author)
  • Denise Horn - , Charité – Universitätsmedizin Berlin (Author)
  • Annette Grüters-Kieslich - , Charité – Universitätsmedizin Berlin (Author)
  • Christoph Klein - , Dr. von Haunersches Kinderspital, München (Author)
  • Stefan Mundlos - , Charité – Universitätsmedizin Berlin (Author)
  • Markus Nöthen - , University of Bonn Medical Center (Author)
  • Olaf Riess - , University of Tübingen (Author)
  • Thomas Meitinger - , Technical University of Munich (Author)
  • Heiko Krude - , Charité – Universitätsmedizin Berlin (Author)
  • Peter M Krawitz - , University of Bonn Medical Center (Author)
  • Tobias Haack - , University of Tübingen (Author)
  • Nadja Ehmke - , Berlin Institute of Health at Charité (Author)
  • Matias Wagner - , Dr. von Haunersches Kinderspital, München (Author)

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 1:50,000. 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.

Details

Original languageEnglish
Pages (from-to)1644-1653
Number of pages10
JournalNature genetics
Volume56
Issue number8
Publication statusPublished - Aug 2024
Peer-reviewedNo

External IDs

PubMedCentral PMC11319204
Scopus 85199186684
ORCID /0009-0003-6519-0482/work/166325416
ORCID /0000-0001-6313-4434/work/166326575

Keywords

Keywords

  • Humans, Phenotype, Female, Male, High-Throughput Nucleotide Sequencing/methods, Child, Germany, Exome Sequencing/methods, Adolescent, Genetic Association Studies/methods, Genetic Testing/methods, Child, Preschool, Prospective Studies, Adult, Neurodevelopmental Disorders/genetics, Infant, Young Adult