Next-generation phenotyping integrated in a national framework for patients with ultra-rare disorders improves genetic diagnostics and yields new molecular findings
Author:
Schmidt AxelORCID, Danyel MagdalenaORCID, Grundmann Kathrin, Brunet TheresaORCID, Klinkhammer HannahORCID, Hsieh Tzung-ChienORCID, Engels Hartmut, Peters Sophia, Knaus AlexejORCID, Moosa ShahidaORCID, Averdunk LuisaORCID, Boschann FelixORCID, Sczakiel HenrikeORCID, Schwartzmann SarinaORCID, Mensah Martin AttaORCID, Pantel Jean ToriORCID, Holtgrewe ManuelORCID, Bösch AnnemarieORCID, Weiß ClaudiaORCID, Weinhold Natalie, Suter Aude-AnnickORCID, Stoltenburg CorinnaORCID, Neugebauer Julia, Kallinich Tillmann, Kaindl Angela M.ORCID, Holzhauer Susanne, Bührer ChristophORCID, Bufler PhilipORCID, Kornak UweORCID, Ott Claus-Eric, Schülke MarkusORCID, Nguyen Hoa Huu PhucORCID, Hoffjan Sabine, Grasemann CorinnaORCID, Rothoeft Tobias, Brinkmann FolkeORCID, Matar Nora, Sivalingam SugirthanORCID, Perne Claudia, Mangold Elisabeth, Kreiss Martina, Cremer Kirsten, Betz Regina C., Bender Tim, Mücke MartinORCID, Grigull LorenzORCID, Klockgether ThomasORCID, Isabel Spier, André Heimbach, Tim Bender, Brand Fabian, Stieber Christiane, Morawiec Alexandra Marzena, Karakostas Pantelis, Schäfer Valentin S.ORCID, Bernsen SarahORCID, Weydt PatrickORCID, Castro-Gomez SergioORCID, Aziz Ahmad, Grobe-Einsler MarcusORCID, Kimmich Okka, Kobeleva Xenia, Önder Demet, Lesmann Hellen, Kumar Sheetal, Tacik Pawel, Lee-Kirsch Min AeORCID, Berner ReinhardORCID, Schuetz CatharinaORCID, Körholz Julia, Kretschmer Tanita, Di Donato NataliyaORCID, Schröck EvelinORCID, Heinen André, Reuner Ulrike, Hanßke Amalia-Mihaela, Kaiser Frank J., Manka Eva, Munteanu MartinORCID, Kuechler Alma, Cordula Kiewert, Hirtz Raphael, Schlapakow Elena, Schlein Christian, Lisfeld Jasmin, Kubisch ChristianORCID, Herget Theresia, Hempel Maja, Weiler-Normann Christina, Ullrich Kurt, Schramm Christoph, Rudolph Cornelia, Rillig Franziska, Groffmann Maximilian, Muntau AniaORCID, Tibelius Alexandra, Schwaibold Eva M. C.ORCID, Schaaf Christian P.ORCID, Zawada Michal, Kaufmann Lilian, Hinderhofer Katrin, Okun Pamela M., Kotzaeridou UraniaORCID, Hoffmann Georg F.ORCID, Choukair DanielaORCID, Bettendorf Markus, Spielmann MalteORCID, Ripke Annekatrin, Pauly MartjeORCID, Münchau AlexanderORCID, Lohmann KatjaORCID, Hüning Irina, Hanker Britta, Bäumer Tobias, Herzog RebeccaORCID, Hellenbroich Yorck, Westphal Dominik S.ORCID, Strom Tim, Kovacs RekaORCID, Riedhammer Korbinian M.ORCID, Mayerhanser Katharina, Graf Elisabeth, Brugger MelanieORCID, Hoefele JuliaORCID, Oexle KonradORCID, Mirza-Schreiber NazaninORCID, Berutti Riccardo, Schatz Ulrich, Krenn MartinORCID, Makowski Christine, Weigand Heike, Schröder Sebastian, Rohlfs MeinoORCID, Katharina VillORCID, Hauck FabianORCID, Borggraefe IngoORCID, Müller-Felber WolfgangORCID, Kurth IngoORCID, Elbracht MiriamORCID, Knopp CordulaORCID, Begemann MatthiasORCID, Kraft FlorianORCID, Lemke Johannes R.ORCID, Hentschel JuliaORCID, Platzer KonradORCID, Strehlow VincentORCID, Jamra Rami AbouORCID, Kehrer Martin, Demidov GermanORCID, Beck-Wödl Stefanie, Graessner HolmORCID, Sturm MarcORCID, Zeltner Lena, Schöls Ludger J.ORCID, Magg Janine, Bevot Andrea, Kehrer Christiane, Kaiser Nadja, Horn Denise, Grüters-Kieslich Annette, Klein Christoph, Mundlos StefanORCID, Nöthen MarkusORCID, Riess OlafORCID, Meitinger ThomasORCID, Krude Heiko, Krawitz Peter M.ORCID, Haack TobiasORCID, Ehmke NadjaORCID, Wagner MatiasORCID
Abstract
AbstractMost 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.
Publisher
Cold Spring Harbor Laboratory
Cited by
6 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|