Next-generation phenotyping integrated in a national framework for patients with ultra-rare 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 , 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. , Bender Tim , Mücke Martin , Grigull Lorenz , Klockgether Thomas , Isabel Spier , André Heimbach , Tim Bender , 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 , 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 , Katharina Vill , 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 , Jamra Rami Abou , Kehrer Martin , Demidov German , Beck-Wödl Stefanie , Graessner Holm , Sturm Marc , Zeltner Lena , Schöls Ludger J. , Magg Janine , Bevot Andrea , Kehrer Christiane , Kaiser Nadja , 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: April 2023

Most individuals with rare diseases initially consult their primary care physician. For a subset of rare diseases, efficient diagnostic pathways are available. However, ultra-rare diseases often require both expert clinical knowledge and comprehensive genetic diagnostics, which poses structural challenges for public healthcare systems. To address these challenges within Germany, a novel structured diagnostic concept, based on multidisciplinary expertise at established university hospital centers for rare diseases (CRDs), was evaluated in the three year prospective study TRANSLATE NAMSE. A key goal of TRANSLATE NAMSE was to assess the clinical value of exome sequencing (ES) in the ultra-rare disease population. The aims of the present study were to perform a systematic investigation of the phenotypic and molecular genetic data of TRANSLATE NAMSE patients who had undergone ES in order to determine the yield of both ultra-rare diagnoses and novel gene-disease associations; and determine whether the complementary use of machine learning and artificial intelligence (AI) tools improved diagnostic effectiveness and efficiency.

ES was performed for 1,577 patients (268 adult and 1,309 pediatric). Molecular genetic diagnoses were established in 499 patients (74 adult and 425 pediatric). A total of 370 distinct molecular genetic causes were established. The majority of these concerned known disorders, most of which were ultra-rare. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were delineated, mainly in individuals with neurodevelopmental disorders.

To determine the likelihood that ES will lead to a molecular diagnosis in a given patient, based on the respective clinical features only, we developed a statistical framework called YieldPred. The genetic data of a subcohort of 224 individuals that also gave consent to the computer-assisted analysis of their facial images were processed with the AI tool Prioritization of Exome Data by Image Analysis (PEDIA) and showed superior performance in variant prioritization.

The present analyses demonstrated that the novel structured diagnostic concept facilitated the identification of ultra-rare genetic disorders and novel gene-disease associations on a national level and that the machine learning and AI tools improved diagnostic effectiveness and efficiency for ultra-rare genetic disorders.