Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
Authors: 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 , Stieber Christiane , Morawiec Alexandra Marzena , Karakostas Pantelis , Schäfer Valentin S. , Bernsen Sarah , Weydt Patrick , Castro-Gomez Sergio , Aziz Ahmad , Grobe-Einsler Marcus , Kimmich Okka , Kobeleva Xenia , Önder Demet , Lesmann Hellen , Kumar Sheetal , Tacik Pawel , Basin Meghna Ahuja , Incardona Pietro , Lee-Kirsch Min Ae , Berner Reinhard , Schuetz Catharina , Körholz Julia , Kretschmer Tanita , Di Donato Nataliya , Schröck Evelin , Heinen André , Reuner Ulrike , Hanßke Amalia-Mihaela , Kaiser Frank J. , Manka Eva , Munteanu Martin , Kuechler Alma , Cordula Kiewert , Hirtz Raphael , Schlapakow Elena , Schlein Christian , Lisfeld Jasmin , Kubisch Christian , Herget Theresia , Hempel Maja , Weiler-Normann Christina , Ullrich Kurt , Schramm Christoph , Rudolph Cornelia , Rillig Franziska , Groffmann Maximilian , Muntau Ania , Tibelius Alexandra , Schwaibold Eva M. C. , Schaaf Christian P. , Zawada Michal , Kaufmann Lilian , Hinderhofer Katrin , Okun Pamela M. , Kotzaeridou Urania , Hoffmann Georg F. , Choukair Daniela , Bettendorf Markus , Spielmann Malte , Ripke Annekatrin , Pauly Martje , Münchau Alexander , Lohmann Katja , Hüning Irina , Hanker Britta , Bäumer Tobias , Herzog Rebecca , Hellenbroich Yorck , Westphal Dominik S. , Strom Tim , Kovacs Reka , Riedhammer Korbinian M. , Mayerhanser Katharina , Graf Elisabeth , Brugger Melanie , Hoefele Julia , Oexle Konrad , Mirza-Schreiber Nazanin , Berutti Riccardo , Schatz Ulrich , Krenn Martin , Makowski Christine , Weigand Heike , Schröder Sebastian , Rohlfs Meino , Vill Katharina , Hauck Fabian , Borggraefe Ingo , Müller-Felber Wolfgang , Kurth Ingo , Elbracht Miriam , Knopp Cordula , Begemann Matthias , Kraft Florian , Lemke Johannes R. , Hentschel Julia , Platzer Konrad , Strehlow Vincent , Abou Jamra Rami , Kehrer Martin , Demidov German , Beck-Wödl Stefanie , Graessner Holm , Sturm Marc , Zeltner Lena , Schöls Ludger J. , Magg Janine , Bevot Andrea , Kehrer Christiane , Kaiser Nadja , Turro Ernest , Horn Denise , Grüters-Kieslich Annette , Klein Christoph , Mundlos Stefan , Nöthen Markus , Riess Olaf , Meitinger Thomas , Krude Heiko , Krawitz Peter M. , Haack Tobias , Ehmke Nadja , Wagner Matias 
Published: July 2024

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.