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

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Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
Nature Genetics ( IF 31.7 ) Pub Date : 2024-07-22 , DOI: 10.1038/s41588-024-01836-1
Axel Schmidt ₁ , Magdalena Danyel _{2,

3} , Kathrin Grundmann ₄ , Theresa Brunet ₅ , Hannah Klinkhammer _{6,

7} , Tzung-Chien Hsieh ₆ , Hartmut Engels ₁ , Sophia Peters ₁ , Alexej Knaus ₆ , Shahida Moosa ₈ , Luisa Averdunk ₉ , Felix Boschann _{2,

3} , Henrike Lisa Sczakiel _{2,

3} , Sarina Schwartzmann ₂ , Martin Atta Mensah _{2,

3} , Jean Tori Pantel _{2,

10} , Manuel Holtgrewe ₁₁ , Annemarie Bösch ₁₂ , Claudia Weiß ₁₂ , Natalie Weinhold ₁₂ , Aude-Annick Suter ₁₂ , Corinna Stoltenburg ₁₂ , Julia Neugebauer ₁₂ , Tillmann Kallinich ₁₂ , Angela M Kaindl _{13,

14,

15} , Susanne Holzhauer ₁₂ , Christoph Bührer ₁₂ , Philip Bufler ₁₂ , Uwe Kornak ₂ , Claus-Eric Ott ₂ , Markus Schülke ₂ , Hoa Huu Phuc Nguyen ₁₆ , Sabine Hoffjan ₁₆ , Corinna Grasemann ₁₇ , Tobias Rothoeft ₁₇ , Folke Brinkmann ₁₇ , Nora Matar ₁₇ , Sugirthan Sivalingam ₁ , Claudia Perne ₁ , Elisabeth Mangold ₁ , Martina Kreiss ₁ , Kirsten Cremer ₁ , Regina C Betz ₁ , Martin Mücke ₁₈ , Lorenz Grigull ₁₈ , Thomas Klockgether ₁₉ , Isabel Spier ₁ , André Heimbach ₁ , Tim Bender ₁₈ , Fabian Brand ₆ , Christiane Stieber ₁₈ , Alexandra Marzena Morawiec ₁₈ , Pantelis Karakostas ₂₀ , Valentin S Schäfer ₂₀ , Sarah Bernsen ₁₈ , Patrick Weydt ₁₉ , Sergio Castro-Gomez ₁₉ , Ahmad Aziz ₁₉ , Marcus Grobe-Einsler ₁₉ , Okka Kimmich ₁₉ , Xenia Kobeleva ₁₉ , Demet Önder ₁₉ , Hellen Lesmann ₁ , Sheetal Kumar ₁ , Pawel Tacik ₁₉ , Meghna Ahuja Basin ₆ , Pietro Incardona ₆ , Min Ae Lee-Kirsch _{21,

22} , Reinhard Berner _{21,

22} , Catharina Schuetz _{21,

22} , Julia Körholz _{21,

22} , Tanita Kretschmer _{21,

22} , Nataliya Di Donato _{21,

23} , Evelin Schröck _{21,

23} , André Heinen _{21,

22} , Ulrike Reuner _{21,

24} , Amalia-Mihaela Hanßke ₂₁ , Frank J Kaiser ₂₅ , Eva Manka ₂₆ , Martin Munteanu ₂₅ , Alma Kuechler ₂₅ , Kiewert Cordula ₂₆ , Raphael Hirtz ₂₆ , Elena Schlapakow ₂₇ , Christian Schlein ₂₈ , Jasmin Lisfeld ₂₈ , Christian Kubisch _{28,

29} , Theresia Herget ₂₈ , Maja Hempel _{28,

29,

30} , Christina Weiler-Normann _{29,

31} , Kurt Ullrich ₂₉ , Christoph Schramm _{29,

31} , Cornelia Rudolph ₂₉ , Franziska Rillig ₂₉ , Maximilian Groffmann ₂₉ , Ania Muntau ₃₂ , Alexandra Tibelius ₃₀ , Eva M C Schwaibold ₃₀ , Christian P Schaaf ₃₀ , Michal Zawada ₃₀ , Lilian Kaufmann ₃₀ , Katrin Hinderhofer ₃₀ , Pamela M Okun ₃₃ , Urania Kotzaeridou ₃₃ , Georg F Hoffmann ₃₃ , Daniela Choukair ₃₃ , Markus Bettendorf ₃₃ , Malte Spielmann ₃₄ , Annekatrin Ripke ₃₅ , Martje Pauly _{36,

37} , Alexander Münchau _{35,

38} , Katja Lohmann ₃₉ , Irina Hüning ₃₄ , Britta Hanker ₄₀ , Tobias Bäumer _{35,

38} , Rebecca Herzog _{35,

36} , Yorck Hellenbroich ₄₁ , Dominik S Westphal ₅ , Tim Strom ₅ , Reka Kovacs ₅ , Korbinian M Riedhammer _{5,

42} , Katharina Mayerhanser ₅ , Elisabeth Graf ₅ , Melanie Brugger ₅ , Julia Hoefele ₅ , Konrad Oexle ₄₃ , Nazanin Mirza-Schreiber ₄₃ , Riccardo Berutti ₄₃ , Ulrich Schatz ₅ , Martin Krenn _{5,

44} , Christine Makowski ₄₅ , Heike Weigand ₄₆ , Sebastian Schröder ₄₆ , Meino Rohlfs ₄₆ , Katharina Vill ₄₆ , Fabian Hauck ₄₆ , Ingo Borggraefe ₄₆ , Wolfgang Müller-Felber ₄₆ , Ingo Kurth ₁₀ , Miriam Elbracht ₁₀ , Cordula Knopp ₁₀ , Matthias Begemann ₁₀ , Florian Kraft ₁₀ , Johannes R Lemke _{47,

48} , Julia Hentschel ₄₇ , Konrad Platzer ₄₇ , Vincent Strehlow ₄₇ , Rami Abou Jamra ₄₇ , Martin Kehrer ₄ , German Demidov ₄ , Stefanie Beck-Wödl ₄ , Holm Graessner ₄₉ , Marc Sturm ₄ , Lena Zeltner ₄₉ , Ludger J Schöls ₅₀ , Janine Magg ₄₉ , Andrea Bevot ₅₁ , Christiane Kehrer ₅₁ , Nadja Kaiser ₅₁ , Ernest Turro ₅₂ , Denise Horn ₂ , Annette Grüters-Kieslich ₅₃ , Christoph Klein ₄₆ , Stefan Mundlos ₂ , Markus Nöthen ₁ , Olaf Riess ₄ , Thomas Meitinger ₅ , Heiko Krude ₅₃ , Peter M Krawitz ₆ , Tobias Haack ₄ , Nadja Ehmke _{2,

3} , Matias Wagner _{5,

43,

46}

Affiliation

Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
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.
Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.
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.
Institute for Medical Genetics, Stellenbosch University, Cape Town, South Africa.
Department of Pediatrics, University Hospital Düsseldorf, Düsseldorf, Germany.
Institute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany.
Core Uni Bioinformatics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
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.
Department of Human Genetics, Ruhr University Bochum, Bochum, Germany.
Department of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany.
Center for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Clinic for Internal Medicine III, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.
Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany.
Institute for Clinical Genetics, University Hospital Carl Gustav Carus, Dresden, Germany.
Department of Neurology, University Hospital Carl Gustav Carus, Dresden, Germany.
Institute of Human Genetics, University Hospital Essen, Essen, Germany.
Department of Pediatrics II, University Hospital Essen, Essen, Germany.
Department of Neurology, University Hospital Halle, Halle, Germany.
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.
I. Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Department of Pediatrics, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Institute of Human Genetics, University Hospital Schleswig-Holstein, Lübeck, Germany.
Center for Rare Diseases, University Hospital Schleswig-Holstein, Lübeck, Germany.
Department of Neurology, University Hospital Schleswig-Holstein, Lübeck, Germany.
Institute for Neurogenetics, University Hospital Schleswig-Holstein, Lübeck, Germany.
Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany.
Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
Institute of Human Genetics, University of Lübeck, Lübeck, Germany.
Department of Human Genetics, University Hospital Schleswig-Holstein, Lübeck, Germany.
Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.
Institute of Neurogenomics, Helmholtz Zentrum München, München, Germany.
Department of Neurology, Medical University of Vienna, Wien, Austria.
Department of Paediatrics, Adolescent Medicine and Neonatology, München, Germany.
Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany.
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany.
Center for Rare Diseases, University of Tübingen, Tübingen, Germany.
Department of Neurology, University of Tübingen, Tübingen, Germany.
Department of Pediatric Neurology and Developmental Medicine, University of Tübingen, Tübingen, Germany.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Berlin Centre for Rare Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany.

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.

中文翻译：

将下一代表型分析纳入国家框架中，用于治疗极罕见疾病，可改善遗传诊断并产生新的分子发现

患有极其罕见疾病的个体对医疗保健系统构成了结构性挑战，因为需要专业的临床知识来建立诊断。在一项为期 3 年的前瞻性研究 TRANSLATE NAMSE 中，我们评估了基于德国多学科专业知识的新颖诊断概念。在这里，我们对 1,577 名患者的表型和分子遗传学数据进行了系统研究，这些患者接受了外显子组测序，并使用下一代表型分析方法进行了部分分析。 32% 的患者进行了分子遗传学诊断，涉及 370 种不同的分子遗传学原因，大多数患病率低于 1:50,000。在诊断过程中，发现了 34 个新的和 23 个候选的基因型-表型关联，主要发生在患有神经发育障碍的个体中。与仅基于临床特征和分子评分的方法相比，同意使用 GestaltMatcher 对其面部图像进行计算机辅助分析的子队列的测序数据可以更有效地进行优先排序。我们的研究证明了使用下一代测序和表型分析在常规医疗保健中诊断极罕见疾病以及多学科团队发现新病因的协同作用。

更新日期：2024-07-22

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