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Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing

Authors
  • Bruel, Ange-Line1
  • Nambot, Sophie1
  • Quéré, Virginie1
  • Vitobello, Antonio1, 2
  • Thevenon, Julien1, 3
  • Assoum, Mirna1
  • Moutton, Sébastien1, 3
  • Houcinat, Nada1, 3
  • Lehalle, Daphné1, 3
  • Jean-Marçais, Nolwenn1, 3
  • Verloès, Alain4, 5
  • Karsenti, Alexandra6
  • Goldenberg, Alice7
  • Jacquette, Aurélia8
  • Jouret, Béatrice9
  • Laudier, Béatrice10
  • Coubes, Christine11
  • Francannet, Christine12
  • Lehalle, Daphné13
  • Geneviève, David11
  • And 30 more
  • 1 Université de Bourgogne-Franche Comté, FHU TRANSLAD, Dijon, France , Dijon (France)
  • 2 Plateau Technique de Biologie, CHU Dijon, Dijon, France , Dijon (France)
  • 3 FHU-TRANSLAD, CHU Dijon Bourgogne, France , CHU Dijon Bourgogne (France)
  • 4 Assistance Publique des Hôpitaux de Paris (AP-HP) Hôpital Robert Debré, Paris, 75019, France , Paris (France)
  • 5 INSERM UMR 1141 - Université de Paris, Paris, 75019, France , Paris (France)
  • 6 Hôpital Armand-Trousseau, Paris, 75012, France , Paris (France)
  • 7 Unité de génétique clinique - CHU de Rouen, 1 Rue de Germont, Rouen Cedex, 76031, France , Rouen Cedex (France)
  • 8 Groupe Hospitalier Pitié-Salpêtrière, APHP, Paris, France , Paris (France)
  • 9 CHU Purpan, Toulouse, France , Toulouse (France)
  • 10 CHRU Orléans, Orléans, France , Orléans (France)
  • 11 Université Montpellier 1, Montpellier, France , Montpellier (France)
  • 12 Centre d’Etude des Malformations Congénitales en Auvergne, Clermont-Ferrand, France , Clermont-Ferrand (France)
  • 13 Département de Génétique Médicale, CH Créteil, Créteil, France , Créteil (France)
  • 14 AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, Paris, France , Paris (France)
  • 15 Centre de Référence “déficiences intellectuelles de causes rares”, Paris, France , Paris (France)
  • 16 Groupe de Recherche Clinique (GRC) “déficience intellectuelle et autisme” UPMC, Paris, France , Paris (France)
  • 17 CHU de Bordeaux, Place Amélie Raba-Léon, Bordeaux Cedex, 33 076, France , Bordeaux Cedex (France)
  • 18 Hôpitaux Universitaires de Strasbourg, Strasbourg, France , Strasbourg (France)
  • 19 Hôpital Le Havre, Le Havre, 76600, France , Le Havre (France)
  • 20 University Paris Sud, Paris, France , Paris (France)
  • 21 Service de Génétique Médicale, Saint Etienne, France , Saint Etienne (France)
  • 22 Hôpital Jeanne de Flandre, CHU Lille, Lille, France , Lille (France)
  • 23 University Hospital of Nancy, Nancy, Vandoeuvre-lès-Nancy, 54000, France , Nancy (France)
  • 24 Amiens University Hospital, Amiens, France , Amiens (France)
  • 25 Service de génétique CH de Chambéry, Chambery, F-38000, France , Chambery (France)
  • 26 Bicêtre Hospital, APHP, Bicêtre, France , Bicêtre (France)
  • 27 Centre Hospitalier Universitaire de Dijon, Dijon, 21079, France , Dijon (France)
  • 28 CHU La Réunion, Saint-Pierre, France , Saint-Pierre (France)
  • 29 Hospices Civils de Lyon, Lyon, France , Lyon (France)
  • 30 Embryologie, et Cytogénétique, Bondy, France , Bondy (France)
  • 31 APHM, CHU Timone Enfants, Marseille, France , Marseille (France)
  • 32 Centre Hospitalier Regional Universitaire Brest, Brest, 29200, France , Brest (France)
  • 33 Service de Génétique, CHRU de Tours, Tours, France , Tours (France)
Type
Published Article
Journal
European Journal of Human Genetics
Publisher
Springer Nature
Publication Date
Jun 23, 2019
Volume
27
Issue
10
Pages
1519–1531
Identifiers
DOI: 10.1038/s41431-019-0442-1
Source
Springer Nature
License
Yellow

Abstract

In clinical exome sequencing (cES), the American College of Medical Genetics and Genomics recommends limiting variant interpretation to established human-disease genes. The diagnostic yield of cES in intellectual disability and/or multiple congenital anomalies (ID/MCA) is currently about 30%. Though the results may seem acceptable for rare diseases, they mean that 70% of affected individuals remain genetically undiagnosed. Further analysis extended to all mutated genes in a research environment is a valuable strategy for improving diagnostic yields. This study presents the results of systematic research reanalysis of negative cES in a cohort of 313 individuals with ID/MCA. We identified 17 new genes not related to human disease, implicated 22 non-OMIM disease-causing genes recently or previously rarely related to disease, and described 1 new phenotype associated with a known gene. Twenty-six candidate genes were identified and are waiting for future recurrence. Overall, we diagnose 15% of the individuals with initial negative cES, increasing the diagnostic yield from 30% to more than 40% (or 46% if strong candidate genes are considered). This study demonstrates the power of such extended research reanalysis to increase scientific knowledge of rare diseases. These novel findings can then be applied in the field of diagnostics.

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