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Original article
Diagnostic strategy in segmentation defect of the vertebrae: a retrospective study of 73 patients
  1. Mathilde Lefebvre1,2,
  2. Anne Dieux-Coeslier3,
  3. Geneviève Baujat4,
  4. Elise Schaefer5,
  5. Saint-Onge Judith2,
  6. Anne Bazin6,
  7. Lucile Pinson7,
  8. Tania Attie-Bitach4,
  9. Clarisse Baumann8,
  10. Melanie Fradin9,
  11. Genevieve Pierquin10,
  12. Sophie Julia11,
  13. Chloé Quélin9,
  14. Bérénice Doray12,
  15. Sylvie Berg12,
  16. Catherine Vincent-Delorme3,
  17. Laetitia Lambert13,
  18. Nadine Bachmann14,
  19. Didier Lacombe15,16,
  20. Bertrand Isidor17,
  21. Nicole Laurent18,
  22. Roume Joelle19,
  23. Patricia Blanchet7,
  24. Sylvie Odent9,
  25. Dominique Kervran20,
  26. Nathalie Leporrier21,
  27. Carine Abel22,
  28. Karine Segers10,
  29. Fabienne Guiliano23,
  30. Emmanuelle Ginglinger-Fabre24,
  31. Angelo Selicorni25,
  32. Alice Goldenberg26,
  33. Salima El Chehadeh5,
  34. Christine Francannet27,
  35. Benedicte Demeer28,
  36. Yannis Duffourd2,
  37. Christel Thauvin-Robinet1,2,
  38. Alain Verloes8,
  39. Valerie Cormier-Daire3,
  40. Jean Baptiste Riviere2,
  41. Laurence Faivre1,2,
  42. Julien Thevenon1,2,29
  1. 1 Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l’Est, FHU-TRANSLAD, CHU Dijon, Dijon, France
  2. 2 GAD EA4271 Génétique des Anomalies du Développement (GAD), Université de Bourgogne, Dijon, Bourgogne, France
  3. 3 Service de Génétique, CHRU Jeanne de Flandre, Lille, France
  4. 4 Département de Génétique, Hôpital Necker Enfants Malades, AP-HP, Paris, France
  5. 5 Service de Génétique, CHU Clermont-Ferrand, Clermont-Ferrand, France
  6. 6 Service de Diagnostic Anténatal, Hôpital René Dubois, Pontoise, France
  7. 7 Service de Génétique, CHU Montpellier, Montpellier, France
  8. 8 Département de Génétique, Hôpital Robert Debré, AP-HP, Paris, France
  9. 9 Service de Génétique, CHU Rennes, Rennes, France
  10. 10 Service de Génétique, CHU Sart Tilman, Liège, France
  11. 11 Service de Génétique, CHU Toulouse, Toulouse, France
  12. 12 Service de Génétique, Hôpital Félix Guyon, CHU La Réunion, Réunion, France
  13. 13 Service de Génétique, CHU de Nancy, Nancy, France
  14. 14 Center for Human Genetics, Bioscientia, Ingelheim, Germany
  15. 15 Service de Génétique, CHU Bordeaux, Bordeaux, France
  16. 16 INSERM U1211, Université de Bordeaux, Bordeaux, France
  17. 17 Service de Génétique, CHU Nantes, Nantes, France
  18. 18 Service d’Anatomie Pathologique, CHU Dijon, Dijon, France
  19. 19 Service de Génétique, Hôpital de Poissy, Poissy, France
  20. 20 Service de Pédiatrie, Hôpital d’Orléans, Orléans, France
  21. 21 Service de Génétique, CHU Caen, Caen, France
  22. 22 Service de Génétique, CHU Lyon, Lyon, France
  23. 23 Service de Génétique, CHU Nice, Nice, France
  24. 24 Service de Génétique, Hôpital de Mulhouse, Mulhouse, France
  25. 25 Ambulatorio di Genetica e Sindromolgia Pediatrica, Azienda Ospedaliera San Gerardo, Monza, Italy
  26. 26 Service de Génétique, CHU Rouen, Rouen, France
  27. 27 Service de Génétique, CHU Strasbourg, Strasbourg, France
  28. 28 Service de Génétique, CHU d’Amiens, Amiens, France
  29. 29 Service de Génétique et Procréation, CHU Grenoble-Alpes, Grenoble, France
  1. Correspondence to Dr. Julien Thevenon, Hopital Couple Enfant, Service de Génétique Clinique, Boulevard de la Chantourne, 38700 La Tronche, France; jthevenon{at}


Background Segmentation defects of the vertebrae (SDV) are non-specific features found in various syndromes. The molecular bases of SDV are not fully elucidated due to the wide range of phenotypes and classification issues. The genes involved are in the Notch signalling pathway, which is a key system in somitogenesis. Here we report on mutations identified in a diagnosis cohort of SDV. We focused on spondylocostal dysostosis (SCD) and the phenotype of these patients in order to establish a diagnostic strategy when confronted with SDV.

Patients and methods We used DNA samples from a cohort of 73 patients and performed targeted sequencing of the five known SCD-causing genes (DLL3, MESP2, LFNG, HES7 and TBX6) in the first 48 patients and whole-exome sequencing (WES) in 28 relevant patients.

Results Ten diagnoses, including four biallelic variants in TBX6, two biallelic variants in LFNG and DLL3, and one in MESP2 and HES7, were made with the gene panel, and two diagnoses, including biallelic variants in FLNB and one variant in MEOX1, were made by WES. The diagnostic yield of the gene panel was 10/73 (13.7%) in the global cohort but 8/10 (80%) in the subgroup meeting the SCD criteria; the diagnostic yield of WES was 2/28 (8%).

Conclusion After negative array CGH, targeted sequencing of the five known SCD genes should only be performed in patients who meet the diagnostic criteria of SCD. The low proportion of candidate genes identified by WES in our cohort suggests the need to consider more complex genetic architectures in cases of SDV.

  • segmentation defect of the vertebrae
  • spondylocostal dysostosis
  • gene panel
  • whole exome sequencing
  • diagnostic strategy

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  • Contributors ML and JT: data analysis and writing of the manuscript. LF and VC-D: revision of the final manuscript. AD-C, GB, ES, AB, LP, TA-B, CB, MF, GP, SJ, CQ, BerD, SB, CV-D, LL, NB, DL, BI, NiL, RJ, PB, SO, DK, NaL, CA, KS, FG, EG-F, AS, AG, SEC, CF, BenD, AV and CT-R: described their patients, and sent X-rays and DNA. YD, SO-J and JBR: panel design, bioinformatic pipeline and sequencing.

  • Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Ethics approval The study was approved by a local ethics committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Candidate genes are shared in GeneMatcher.