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

medRxiv

Abstract

Abstract 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.

Authors 100

1. Axel Schmidt

   University of Bonn · University Hospital Bonn

   Affiliation as printed

   Institute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

2. Magdalena Danyel

   Berlin Institute of Health at Charité - Universitätsmedizin Berlin · Charité - Universitätsmedizin Berlin

   Affiliation as printed

   BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany

   Institute for Medical Genetics and Human Genetics, Charité University Medicine Berlin, Berlin, Germany

3. Kathrin Grundmann

   University of Tübingen

   Affiliation as printed

   Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany

4. Theresa Brunet

   TUM Klinikum · Institut für Humangenetik · Technical University of Munich

   Affiliation as printed

   Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany

5. Hannah Klinkhammer

   University of Bonn · University Hospital Bonn · Institut für Medizinische Biometrie, Informatik und Epidemiologie

   Affiliation as printed

   Institut für Medizinische Biometrie, Informatik und Epidemiologie, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

   Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

6. Tzung‐Chien Hsieh

   University of Bonn · University Hospital Bonn

   Affiliation as printed

   Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

7. Hartmut Engels

   University of Bonn · University Hospital Bonn

   Affiliation as printed

   Institute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

8. Sophia Peters

   University of Bonn · University Hospital Bonn

   Affiliation as printed

   Institute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

9. Alexej Knaus

   University of Bonn · University Hospital Bonn

   Affiliation as printed

   Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

10. Shahida Moosa

    Stellenbosch University

    Affiliation as printed

    Institute for Medical Genetics, Stellenbosch University, Cape Town, South Africa

11. Luisa Averdunk

    Düsseldorf University Hospital

    Affiliation as printed

    Department of Pediatrics, University Hospital Düsseldorf, Düsseldorf, Germany

12. Felix Boschann

    Berlin Institute of Health at Charité - Universitätsmedizin Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany

    Institute for Medical Genetics and Human Genetics, Charité University Medicine Berlin, Berlin, Germany

13. Henrike L. Sczakiel

    Berlin Institute of Health at Charité - Universitätsmedizin Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany

    Institute for Medical Genetics and Human Genetics, Charité University Medicine Berlin, Berlin, Germany

14. Sarina Schwartzmann

    Berlin Institute of Health at Charité - Universitätsmedizin Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany

    Institute for Medical Genetics and Human Genetics, Charité University Medicine Berlin, Berlin, Germany

15. Martin A. Mensah

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Institute for Medical Genetics and Human Genetics, Charité University Medicine Berlin, Berlin, Germany

16. Jean Tori Pantel Aachen Institute for Human Genetics and Genomic Medicine Medical Faculty

    Universitätsklinikum Aachen · Charité - Universitätsmedizin Berlin · RWTH Aachen University

    Affiliation as printed

    Institute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany

    Institute for Medical Genetics and Human Genetics, Charité University Medicine Berlin, Berlin, Germany

17. Manuel Holtgrewe

    Berlin Institute of Health at Charité - Universitätsmedizin Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Core Uni Bioinformatics (CUBI), Berlin Institute of Health at Charité University Medicine Berlin, Berlin, Germany

18. Annemarie Bösch

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Department of Pediatrics, Charité University Medicine Berlin, Berlin, Germany

19. Claudia Weiß

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Department of Pediatrics, Charité University Medicine Berlin, Berlin, Germany

20. Natalie Weinhold

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Department of Pediatrics, Charité University Medicine Berlin, Berlin, Germany

21. Aude‐Annick Suter

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Department of Pediatrics, Charité University Medicine Berlin, Berlin, Germany

22. Corinna Stoltenburg

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Department of Pediatrics, Charité University Medicine Berlin, Berlin, Germany

23. Julia Neugebauer

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Department of Pediatrics, Charité University Medicine Berlin, Berlin, Germany

24. Tillmann Kallinich

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Department of Pediatrics, Charité University Medicine Berlin, Berlin, Germany

25. Angela Maria Kaindl

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Center for Chronically Sick Children, Charité University Medicine Berlin, Berlin, Germany

    Department of Pediatric Neurulogy, Charité University Medicine Berlin, Berlin, Germany

    Institute of Cell- and Neurobiology, Charité University Medicine Berlin, Berlin, Germany

26. Susanne Holzhauer

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Department of Pediatrics, Charité University Medicine Berlin, Berlin, Germany

27. Christoph Bührer

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Department of Pediatrics, Charité University Medicine Berlin, Berlin, Germany

28. Philip Bufler

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Department of Pediatrics, Charité University Medicine Berlin, Berlin, Germany

29. Uwe Kornak

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Institute for Medical Genetics and Human Genetics, Charité University Medicine Berlin, Berlin, Germany

30. Claus‐Eric Ott

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Institute for Medical Genetics and Human Genetics, Charité University Medicine Berlin, Berlin, Germany

31. Markus Schülke

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Institute for Medical Genetics and Human Genetics, Charité University Medicine Berlin, Berlin, Germany

32. Huu Phuc Nguyen

    Ruhr University Bochum

    Affiliation as printed

    Department of Human Genetics, Ruhr University Bochum, Bochum, Germany

33. Sabine Hoffjan

    Ruhr University Bochum

    Affiliation as printed

    Department of Human Genetics, Ruhr University Bochum, Bochum, Germany

34. Corinna Grasemann

    Ruhr University Bochum

    Affiliation as printed

    Department of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany

35. Tobias Rothoeft

    Ruhr University Bochum

    Affiliation as printed

    Department of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany

36. Folke Brinkmann

    Ruhr University Bochum

    Affiliation as printed

    Department of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany

37. Nora Matar

    Ruhr University Bochum

    Affiliation as printed

    Department of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany

38. Sugirthan Sivalingam

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Institute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

39. Claudia Perne

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Institute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

40. Elisabeth Mangold

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Institute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

41. Martina Kreiß

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Institute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

42. Kirsten Cremer

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Institute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

43. Regina Christine Betz

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Institute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

44. Tim Th. A. Bender

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Institute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

45. Martin Mücke

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Center for Rare Diseases, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

46. Lorenz Grigull

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Center for Rare Diseases, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

47. Thomas Klockgether

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Department of Neurology, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

48. Spier Isabel

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Institute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

49. Heimbach André

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Institute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

50. Bender Tim

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Center for Rare Diseases, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

51. Fabian Brand

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

52. Christiane Stieber

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Center for Rare Diseases, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

53. Alexandra Marzena Morawiec

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Center for Rare Diseases, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

54. Pantelis Karakostas

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Clinic fof Internal Medicine III, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

55. Valentin Sebastian Schäfer

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Clinic fof Internal Medicine III, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

56. Sarah Bernsen

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Center for Rare Diseases, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

57. Patrick Weydt

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Department of Neurology, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

58. Sergio Castro‐Gomez

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Department of Neurology, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

59. Ahmad Aziz

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Department of Neurology, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

60. Marcus Grobe‐Einsler

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Department of Neurology, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

61. Okka Kimmich

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Department of Neurology, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

62. Xenia Kobeleva

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Department of Neurology, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

63. Demet Önder

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Department of Neurology, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

64. Hellen Lesmann

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Institute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

65. Sheetal Kumar

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Institute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

66. Pawel M. Tacik

    University of Bonn · University Hospital Bonn

    Affiliation as printed

    Department of Neurology, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany

67. Min Ae Lee‐Kirsch

    University Hospital Carl Gustav Carus

    Affiliation as printed

    Department Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany

    University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany

68. Reinhard Berner

    University Hospital Carl Gustav Carus

    Affiliation as printed

    Department Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany

    University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany

69. Catharina Schuetz

    University Hospital Carl Gustav Carus

    Affiliation as printed

    Department Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany

    University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany

70. Julia C Körholz

    University Hospital Carl Gustav Carus

    Affiliation as printed

    Department Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany

    University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany

71. Tanita Kretschmer

    University Hospital Carl Gustav Carus

    Affiliation as printed

    Department Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany

    University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany

72. Nataliya Di Donato

    University Hospital Carl Gustav Carus

    Affiliation as printed

    Institute for Clinical Genetics, University Hospital Carl Gustav Carus, Dresden, Germany

    University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany

73. Evelin Schröck

    University Hospital Carl Gustav Carus

    Affiliation as printed

    Institute for Clinical Genetics, University Hospital Carl Gustav Carus, Dresden, Germany

    University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany

74. André Heinen

    University Hospital Carl Gustav Carus

    Affiliation as printed

    Department Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany

    University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany

75. Ulrike Reuner

    University Hospital Carl Gustav Carus

    Affiliation as printed

    Department of Neurology, University Hospital Carl Gustav Carus, Dresden, Germany

    University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany

76. Amalia-Mihaela Hanßke

    University Hospital Carl Gustav Carus

    Affiliation as printed

    University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany

77. Frank J. Kaiser

    Essen University Hospital

    Affiliation as printed

    Institute of Human Genetics, University Hospital Essen, Essen, Germany

78. Eva Manka

    Essen University Hospital

    Affiliation as printed

    Department of Pediatrics II, University Hospital Essen, Essen, Germany

79. Martin Munteanu

    Essen University Hospital

    Affiliation as printed

    Institute of Human Genetics, University Hospital Essen, Essen, Germany

80. Alma Kuechler

    Essen University Hospital

    Affiliation as printed

    Institute of Human Genetics, University Hospital Essen, Essen, Germany

81. Cordula Kiewert

    Essen University Hospital

    Affiliation as printed

    Department of Pediatrics II, University Hospital Essen, Essen, Germany

82. Raphael Hirtz

    Essen University Hospital

    Affiliation as printed

    Department of Pediatrics II, University Hospital Essen, Essen, Germany

83. Elena Schlapakow

    University Hospital in Halle

    Affiliation as printed

    Department of Neurology, University Hospital Halle, Halle, Germany

84. Christian Schlein

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Institute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany

85. Jasmin Lisfeld

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Institute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany

86. Christian Kubisch

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Institute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany

87. Theresia Herget

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Institute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany

88. Maja Hempel

    Heidelberg University · University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Institute of Human Genetics, Heidelberg University, Heidelberg, Germany

    Institute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany

89. Christina Weiler‐Normann

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    I. Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany

90. Kurt Ullrich

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany

91. Christoph Schramm

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    I. Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany

92. Cornelia Rudolph

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany

93. Franziska Rillig

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany

94. Maximilian Groffmann

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany

95. Ania Carolina Muntau

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Department of Pediatrics, University Hospital Hamburg-Eppendorf, Hamburg, Germany

96. Alexandra Tibelius

    Heidelberg University

    Affiliation as printed

    Institute of Human Genetics, Heidelberg University, Heidelberg, Germany

97. Eva Maria Christina Schwaibold

    Heidelberg University

    Affiliation as printed

    Institute of Human Genetics, Heidelberg University, Heidelberg, Germany

98. Christian Patrick Schaaf

    Heidelberg University

    Affiliation as printed

    Institute of Human Genetics, Heidelberg University, Heidelberg, Germany

99. Michal Zawada

    Heidelberg University

    Affiliation as printed

    Institute of Human Genetics, Heidelberg University, Heidelberg, Germany

100. Lilian Tamara Kaufmann

     Heidelberg University

     Affiliation as printed

     Institute of Human Genetics, Heidelberg University, Heidelberg, Germany