Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
Axel Schmidt, Magdalena Danyel, Kathrin Grundmann, Theresa Brunet, Hannah Klinkhammer, Tzung‐Chien Hsieh, Hartmut Engels, Sophia Peters, Alexej Knaus, Shahida Moosa, Luisa Averdunk, Felix Boschann, Henrike L. Sczakiel, Sarina Schwartzmann, Martin A. Mensah, Jean Tori Pantel, Manuel Holtgrewe, Annemarie Bösch, Claudia Weiß, Natalie Weinhold, Aude‐Annick Suter, Corinna Stoltenburg, Julia Neugebauer, Tillmann Kallinich, Angela M. Kaindl, Susanne Holzhauer, Christoph Bührer, Philip Bufler, Uwe Kornak, Claus‐Eric Ott, Markus Schülke, Hoa Huu Phuc Nguyen, Sabine Hoffjan, Corinna Grasemann, Tobias Rothoeft, Folke Brinkmann, Nora Matar, Sugirthan Sivalingam, Claudia Perne, Elisabeth Mangold, Martina Kreiß, Kirsten Cremer, Regina C. Betz, Martin Mücke, Lorenz Grigull, Thomas Klockgether, Isabel Spier, André Heimbach, Tim Bender, Fabian Brand, Christiane Stieber, Alexandra Marzena Morawiec, Pantelis Karakostas, Valentin Sebastian Schäfer, Sarah Bernsen, Patrick Weydt, Sergio Castro‐Gomez, Ahmad Aziz, Marcus Grobe‐Einsler, Okka Kimmich, Xenia Kobeleva, Demet Önder, Hellen Lesmann, Sheetal Kumar, Paweł Tacik, Meghna Ahuja Bhasin, Pietro Incardona, Min Ae Lee‐Kirsch, Reinhard Berner, Catharina Schuetz, Julia Körholz, Tanita Kretschmer, Nataliya Di Donato, Evelin Schröck, A. Heinen, Ulrike Reuner, Amalia-Mihaela Hanßke, Frank J. Kaiser, Eva Manka, Martin Munteanu, Alma Kuechler, Cordula Kiewert, Raphael Hirtz, Elena Schlapakow, Christian Schlein, Jasmin Lisfeld, Christian Kubisch, Theresia Herget, Maja Hempel, Christina Weiler‐Normann, Kurt Ullrich, Christoph Schramm, Cornelia Rudolph, Franziska Rillig, Maximilian Groffmann, Ania C. Muntau, Alexandra Tibelius, Eva Maria Christina Schwaibold, Christian P. Schaaf, Michal Zawada
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.