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

Autor:	Schmidt A; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Danyel M; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.; BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Grundmann K; Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Brunet T; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Klinkhammer H; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.; Institut für Medizinische Biometrie, Informatik und Epidemiologie, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Hsieh TC; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Engels H; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Peters S; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Knaus A; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Moosa S; Institute for Medical Genetics, Stellenbosch University, Cape Town, South Africa., Averdunk L; Department of Pediatrics, University Hospital Düsseldorf, Düsseldorf, Germany., Boschann F; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.; BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Sczakiel HL; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.; BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Schwartzmann S; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Mensah MA; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.; BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Pantel JT; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.; Institute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany., Holtgrewe M; Core Uni Bioinformatics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Bösch A; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Weiß C; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Weinhold N; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Suter AA; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Stoltenburg C; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Neugebauer J; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Kallinich T; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Kaindl AM; Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.; Center for Chronically Sick Children, Charité - Universitätsmedizin Berlin, Berlin, Germany.; Institute of Cell and Neurobiology, Charité - Universitätsmedizin Berlin, Berlin, Germany., Holzhauer S; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Bührer C; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Bufler P; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Kornak U; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Ott CE; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Schülke M; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Nguyen HHP; Department of Human Genetics, Ruhr University Bochum, Bochum, Germany., Hoffjan S; Department of Human Genetics, Ruhr University Bochum, Bochum, Germany., Grasemann C; Department of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany., Rothoeft T; Department of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany., Brinkmann F; Department of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany., Matar N; Department of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany., Sivalingam S; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Perne C; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Mangold E; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Kreiss M; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Cremer K; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Betz RC; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Mücke M; Center for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Grigull L; Center for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Klockgether T; Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Spier I; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Heimbach A; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Bender T; Center for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Brand F; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Stieber C; Center for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Morawiec AM; Center for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Karakostas P; Clinic for Internal Medicine III, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Schäfer VS; Clinic for Internal Medicine III, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Bernsen S; Center for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Weydt P; Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Castro-Gomez S; Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Aziz A; Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Grobe-Einsler M; Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Kimmich O; Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Kobeleva X; Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Önder D; Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Lesmann H; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Kumar S; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Tacik P; Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Basin MA; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Incardona P; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Lee-Kirsch MA; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.; Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany., Berner R; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.; Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany., Schuetz C; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.; Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany., Körholz J; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.; Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany., Kretschmer T; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.; Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany., Di Donato N; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.; Institute for Clinical Genetics, University Hospital Carl Gustav Carus, Dresden, Germany., Schröck E; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.; Institute for Clinical Genetics, University Hospital Carl Gustav Carus, Dresden, Germany., Heinen A; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.; Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany., Reuner U; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.; Department of Neurology, University Hospital Carl Gustav Carus, Dresden, Germany., Hanßke AM; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany., Kaiser FJ; Institute of Human Genetics, University Hospital Essen, Essen, Germany., Manka E; Department of Pediatrics II, University Hospital Essen, Essen, Germany., Munteanu M; Institute of Human Genetics, University Hospital Essen, Essen, Germany., Kuechler A; Institute of Human Genetics, University Hospital Essen, Essen, Germany., Cordula K; Department of Pediatrics II, University Hospital Essen, Essen, Germany., Hirtz R; Department of Pediatrics II, University Hospital Essen, Essen, Germany., Schlapakow E; Department of Neurology, University Hospital Halle, Halle, Germany., Schlein C; Institute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Lisfeld J; Institute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Kubisch C; Institute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany.; Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Herget T; Institute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Hempel M; Institute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany.; Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany.; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Weiler-Normann C; Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany.; I. Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Ullrich K; Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Schramm C; Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany.; I. Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Rudolph C; Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Rillig F; Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Groffmann M; Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Muntau A; Department of Pediatrics, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Tibelius A; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Schwaibold EMC; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Schaaf CP; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Zawada M; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Kaufmann L; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Hinderhofer K; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Okun PM; Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany., Kotzaeridou U; Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany., Hoffmann GF; Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany., Choukair D; Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany., Bettendorf M; Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany., Spielmann M; Institute of Human Genetics, University Hospital Schleswig-Holstein, Lübeck, Germany., Ripke A; Center for Rare Diseases, University Hospital Schleswig-Holstein, Lübeck, Germany., Pauly M; Department of Neurology, University Hospital Schleswig-Holstein, Lübeck, Germany.; Institute for Neurogenetics, University Hospital Schleswig-Holstein, Lübeck, Germany., Münchau A; Center for Rare Diseases, University Hospital Schleswig-Holstein, Lübeck, Germany.; Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany., Lohmann K; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany., Hüning I; Institute of Human Genetics, University Hospital Schleswig-Holstein, Lübeck, Germany., Hanker B; Institute of Human Genetics, University of Lübeck, Lübeck, Germany., Bäumer T; Center for Rare Diseases, University Hospital Schleswig-Holstein, Lübeck, Germany.; Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany., Herzog R; Center for Rare Diseases, University Hospital Schleswig-Holstein, Lübeck, Germany.; Department of Neurology, University Hospital Schleswig-Holstein, Lübeck, Germany., Hellenbroich Y; Department of Human Genetics, University Hospital Schleswig-Holstein, Lübeck, Germany., Westphal DS; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Strom T; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Kovacs R; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Riedhammer KM; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.; Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Mayerhanser K; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Graf E; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Brugger M; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Hoefele J; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Oexle K; Institute of Neurogenomics, Helmholtz Zentrum München, München, Germany., Mirza-Schreiber N; Institute of Neurogenomics, Helmholtz Zentrum München, München, Germany., Berutti R; Institute of Neurogenomics, Helmholtz Zentrum München, München, Germany., Schatz U; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Krenn M; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.; Department of Neurology, Medical University of Vienna, Wien, Austria., Makowski C; Department of Paediatrics, Adolescent Medicine and Neonatology, München, Germany., Weigand H; Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany., Schröder S; Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany., Rohlfs M; Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany., Vill K; Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany., Hauck F; Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany., Borggraefe I; Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany., Müller-Felber W; Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany., Kurth I; Institute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany., Elbracht M; Institute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany., Knopp C; Institute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany., Begemann M; Institute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany., Kraft F; Institute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany., Lemke JR; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.; Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany., Hentschel J; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Platzer K; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Strehlow V; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Abou Jamra R; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Kehrer M; Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Demidov G; Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Beck-Wödl S; Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Graessner H; Center for Rare Diseases, University of Tübingen, Tübingen, Germany., Sturm M; Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Zeltner L; Center for Rare Diseases, University of Tübingen, Tübingen, Germany., Schöls LJ; Department of Neurology, University of Tübingen, Tübingen, Germany., Magg J; Center for Rare Diseases, University of Tübingen, Tübingen, Germany., Bevot A; Department of Pediatric Neurology and Developmental Medicine, University of Tübingen, Tübingen, Germany., Kehrer C; Department of Pediatric Neurology and Developmental Medicine, University of Tübingen, Tübingen, Germany., Kaiser N; Department of Pediatric Neurology and Developmental Medicine, University of Tübingen, Tübingen, Germany., Turro E; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Horn D; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Grüters-Kieslich A; Berlin Centre for Rare Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany., Klein C; Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany., Mundlos S; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Nöthen M; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Riess O; Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Meitinger T; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Krude H; Berlin Centre for Rare Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany., Krawitz PM; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany. pkrawitz@uni-bonn.de., Haack T; Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Ehmke N; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.; BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Wagner M; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.; Institute of Neurogenomics, Helmholtz Zentrum München, München, Germany.; Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany.
Jazyk:	angličtina
Zdroj:	Nature genetics [Nat Genet] 2024 Aug; Vol. 56 (8), pp. 1644-1653. Date of Electronic Publication: 2024 Jul 22.
DOI:	10.1038/s41588-024-01836-1
Abstrakt:	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. (© 2024. The Author(s).)
Databáze:	MEDLINE
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