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A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement
  1. Megana K Prasad1,
  2. Véronique Geoffroy1,
  3. Serge Vicaire2,
  4. Bernard Jost2,
  5. Michael Dumas2,
  6. Stéphanie Le Gras2,
  7. Marzena Switala3,4,
  8. Barbara Gasse5,
  9. Virginie Laugel-Haushalter6,
  10. Marie Paschaki1,6,
  11. Bruno Leheup7,
  12. Dominique Droz8,
  13. Amelie Dalstein8,
  14. Adeline Loing3,
  15. Bruno Grollemund4,
  16. Michèle Muller-Bolla9,10,
  17. Séréna Lopez-Cazaux11,
  18. Maryline Minoux3,4,
  19. Sophie Jung3,4,
  20. Frédéric Obry3,4,
  21. Vincent Vogt3,4,
  22. Jean-Luc Davideau4,
  23. Tiphaine Davit-Beal5,12,
  24. Anne-Sophie Kaiser13,
  25. Ute Moog13,
  26. Béatrice Richard14,
  27. Jean-Jacques Morrier14,
  28. Jean-Pierre Duprez14,
  29. Sylvie Odent15,
  30. Isabelle Bailleul-Forestier16,
  31. Monique Marie Rousset17,
  32. Laure Merametdijan18,
  33. Annick Toutain19,
  34. Clara Joseph20,
  35. Fabienne Giuliano21,
  36. Jean-Christophe Dahlet3,
  37. Aymeric Courval22,
  38. Mustapha El Alloussi23,
  39. Samir Laouina23,
  40. Sylvie Soskin24,
  41. Nathalie Guffon25,
  42. Anne Dieux26,
  43. Bérénice Doray27,
  44. Stephanie Feierabend28,
  45. Emmanuelle Ginglinger29,
  46. Benjamin Fournier30,31,
  47. Muriel de la Dure Molla30,31,
  48. Yves Alembik27,
  49. Corinne Tardieu32,
  50. François Clauss3,4,
  51. Ariane Berdal30,31,
  52. Corinne Stoetzel1,
  53. Marie Cécile Manière3,4,
  54. Hélène Dollfus1,33,
  55. Agnès Bloch-Zupan3,4,6
  1. 1Laboratoire de Génétique Médicale, INSERM U1112, Institut de génétique médicale d'Alsace, FMTS, Université de Strasbourg, Strasbourg, France
  2. 2Plateforme de Biopuces et Séquençage, Institut de Génétique et de Biologie Moléculaire and Cellulaire-Centre Européen de Recherche en Biologie et en Médecine, CNRS UMR7104, INSERM U964, Université de Strasbourg, Illkirch, France
  3. 3Centre de Référence des Manifestations Odontologiques des Maladies Rares, Pôle de Médecine et Chirurgie Bucco-dentaires, Hôpitaux Universitaires de Strasbourg (HUS), Strasbourg, France
  4. 4Faculté de Chirurgie Dentaire, Université de Strasbourg, Strasbourg, France
  5. 5Evolution et Développement du Squelette-EDS, UMR7138-SAE, Université Pierre et Marie Curie, Paris, France
  6. 6Institut de Génétique et de Biologie Moléculaire and Cellulaire-Centre Européen de Recherche en Biologie et en Médecine, CNRS UMR7104, INSERM U964 Université de Strasbourg, Illkirch, France
  7. 7Faculté de Médecine, CHU de Nancy, Université de Lorraine, Vandoeuvre-Les-Nancy, France
  8. 8CHU de Nancy, Service d'Odontologie, Nancy, France
  9. 9Départment d'Odontologie Pédiatrique, UFR d'Odontologie, Université de Nice Sophia-Antipolis, CHU de Nice, Nice, France
  10. 10URB2i—EA 4462, Paris Descartes, Paris, France
  11. 11Faculté de Chirurgie Dentaire, Département d'Odontologie Pédiatrique, CHU Hotel Dieu, Service d'odontologie conservatrice et pédiatrique, Nantes, France
  12. 12Faculté de Chirurgie Dentaire, Département d'Odontologie Pédiatrique, Université Paris Descartes, Montrouge, France
  13. 13Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
  14. 14Service de Consultations et Traitements Dentaires, Hospices Civils de Lyon, Faculté d'Odontologie, Université Claude Bernard Lyon1, Lyon, France
  15. 15Service de Génétique Clinique, CHU de Rennes, Rennes, France
  16. 16Faculté de Chirurgie Dentaire, CHU de Toulouse, Odontologie Pédiatrique, Université Paul Sabatier, Toulouse, France
  17. 17Unité Fonctionnelle d'Odontologie pédiatrique, Service d'odontologie, CHRU de Lille, Lille, France
  18. 18Faculté de Chirurgie Dentaire, Service d'Odontologie Conservatrice et Endodontie, CHU Nantes, Université de Nantes, France
  19. 19Service de Génétique, CHU Tours, Tours, France
  20. 20Départment d'Odontologie Pédiatrique, Université de Nice Sophia-Antipolis, CHU Nice, Nice, France
  21. 21Service de Génétique Médicale, CHU Nice, Nice, France
  22. 22Pôle de Médecine et de Chirurgie Bucco-dentaire, Hôpital Civil, HUS, Strasbourg, France
  23. 23Faculty of Dental Medicine, Department of Pediatric Dentistry, University Mohammed V Rabat, Morocco
  24. 24Pédiatrie 1, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  25. 25Département de Pédiatrie, CHU de Lyon, Lyon, France
  26. 26Service de génétique clinique Guy Fontaine, Centre Hospitalier Régionale Universitaire (CHRU) de Lille, Lille, France
  27. 27Service de Génétique Médicale, CHU de Strasbourg, Strasbourg, France
  28. 28Klinik für Zahnerhaltungskunde und Parodontologie, Universitats Klinikum, Freiburg, Germany
  29. 29Service de Génétique, Centre Hospitalier de Mulhouse, Mulhouse, France
  30. 30Laboratoire de Physiopathologie Orale Moléculaire INSERM UMR S1138, Centre de Recherche des Cordeliers, Universités Paris-Diderot et Paris-Descartes, Paris, France
  31. 31Centre de Référence des Malformations Rares de la Face et de la Cavité Buccale MAFACE, Hôpital Rothschild, Pôle d'Odontologie, Paris, France
  32. 32Aix-Marseille Université, UMR 7268 ADES/EFS/CNRS, APHM, Hôpital Timone, Service Odontologie, Marseille, France
  33. 33Service de Génétique Médicale, Centre de Référence pour les Affections Rares en Génétique Ophtalmologique, HUS, Strasbourg, France
  1. Correspondence to Professor Agnès Bloch-Zupan, Faculty of Dentistry , University of Strasbourg, 8 rue St Elisabeth, Strasbourg 67000, France; agnes.bloch-zupan{at}


Background Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders.

Methods We designed an NGS gene panel that targets 585 known and candidate genes in orodental disease. We screened a cohort of 101 unrelated patients without a molecular diagnosis referred to the Reference Centre for Oro-Dental Manifestations of Rare Diseases, Strasbourg, France, for a variety of orodental disorders including isolated and syndromic amelogenesis imperfecta (AI), isolated and syndromic selective tooth agenesis (STHAG), isolated and syndromic dentinogenesis imperfecta, isolated dentin dysplasia, otodental dysplasia and primary failure of tooth eruption.

Results We discovered 21 novel pathogenic variants and identified the causative mutation in 39 unrelated patients in known genes (overall diagnostic rate: 39%). Among the largest subcohorts of patients with isolated AI (50 unrelated patients) and isolated STHAG (21 unrelated patients), we had a definitive diagnosis in 14 (27%) and 15 cases (71%), respectively. Surprisingly, COL17A1 mutations accounted for the majority of autosomal-dominant AI cases.

Conclusions We have developed a novel targeted NGS assay for the efficient molecular diagnosis of a wide variety of orodental diseases. Furthermore, our panel will contribute to better understanding the contribution of these genes to orodental disease.

Trial registration numbers NCT01746121 and NCT02397824.

  • Genetics
  • Diagnostics tests
  • Molecular genetics
  • Genetic screening/counselling
  • Genome-wide

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