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Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders
  1. Caroline Schluth-Bolard1,2,
  2. Flavie Diguet1,2,
  3. Nicolas Chatron1,2,
  4. Pierre-Antoine Rollat-Farnier1,
  5. Claire Bardel3,
  6. Alexandra Afenjar4,5,
  7. Florence Amblard6,
  8. Jeanne Amiel7,
  9. Sophie Blesson8,
  10. Patrick Callier9,
  11. Yline Capri10,
  12. Patrick Collignon11,
  13. Marie-Pierre Cordier1,
  14. Christine Coubes12,
  15. Benedicte Demeer13,
  16. Annabelle Chaussenot14,
  17. Florence Demurger15,
  18. Françoise Devillard6,
  19. Martine Doco-Fenzy16,
  20. Céline Dupont10,
  21. Jean-Michel Dupont17,
  22. Sophie Dupuis-Girod1,
  23. Laurence Faivre18,
  24. Brigitte Gilbert-Dussardier19,
  25. Anne-Marie Guerrot20,
  26. Marine Houlier7,
  27. Bertrand Isidor21,
  28. Sylvie Jaillard22,
  29. Géraldine Joly-Hélas23,
  30. Valérie Kremer24,
  31. Didier Lacombe25,
  32. Cédric Le Caignec21,
  33. Aziza Lebbar17,
  34. Marine Lebrun26,
  35. Gaetan Lesca1,2,
  36. James Lespinasse27,
  37. Jonathan Levy10,
  38. Valérie Malan28,
  39. Michele Mathieu-Dramard13,
  40. Julie Masson1,2,
  41. Alice Masurel-Paulet18,
  42. Cyril Mignot29,
  43. Chantal Missirian30,
  44. Fanny Morice-Picard25,
  45. Sébastien Moutton25,
  46. Gwenaël Nadeau27,31,
  47. Céline Pebrel-Richard32,
  48. Sylvie Odent15,33,
  49. Véronique Paquis-Flucklinger14,
  50. Laurent Pasquier15,
  51. Nicole Philip34,
  52. Morgane Plutino14,
  53. Linda Pons1,2,
  54. Marie-France Portnoï4,
  55. Fabienne Prieur26,
  56. Jacques Puechberty12,
  57. Audrey Putoux1,2,
  58. Marlène Rio7,
  59. Caroline Rooryck-Thambo25,
  60. Massimiliano Rossi1,2,
  61. Catherine Sarret35,
  62. Véronique Satre6,36,
  63. Jean-Pierre Siffroi4,
  64. Marianne Till1,
  65. Renaud Touraine26,
  66. Annick Toutain8,
  67. Jérome Toutain25,
  68. Stéphanie Valence5,37,
  69. Alain Verloes10,
  70. Sandra Whalen4,
  71. Patrick Edery1,2,
  72. Anne-Claude Tabet10,
  73. Damien Sanlaville1,2
  1. 1 Service de Génétique, Hospices Civils de Lyon, Bron, France
  2. 2 INSERM U1028, CNRS UMR5292, UCBL1, GENDEV Team, Neurosciences Research Center of Lyon, Bron, France
  3. 3 Cellule bioinformatique de la plateforme NGS, Hospices Civils de Lyon, CNRS, Laboratoire de Biométrie et Biologie Evolutive UMR5558, Lyon 1 University, Bron, France
  4. 4 Département de génétique et embryologie médicale, Centre de référence des déficiences intellectuelles de causes rares, AP-HP, Hôpital Armand Trousseau, Paris, France
  5. 5 GRC n°19, pathologies Congénitales du Cervelet-LeucoDystrophies, AP-HP, Hôpital Armand Trousseau, Sorbonne Université, Paris, France
  6. 6 Laboratoire de Génétique Chromosomique, Hôpital Couple Enfant, CHU Grenoble, Grenoble, France
  7. 7 Service de Génétique Médicale, Hôpital Necker-Enfants Malades, Paris, France
  8. 8 Service de Génétique, CHRU de Tours, Tours, France
  9. 9 Laboratoire de Cytogénétique, CHU Dijon, Dijon, France
  10. 10 Département de Génétique, Hôpital Robert Debré, Paris, France
  11. 11 Service de Génétique Médicale, CHI Toulon, Toulon, France
  12. 12 Service de Génétique, Hôpital Arnaud de Villeneuve, Montpellier, France
  13. 13 Centre d’activité de génétique clinique, CLAD nord de France, CHU Amiens, Amiens, France
  14. 14 Service de Génétique Médicale, CHU Nice, Nice, France
  15. 15 Service de Génétique Clinique, CHU Rennes, Rennes, France
  16. 16 Service de Génétique, EA3801, SFR CAP SANTE, CHU Reims, Reims, France
  17. 17 Laboratoire de Cytogénétique Constitutionnelle, APHP-HUPC site Cochin, Paris, France
  18. 18 Centre de référence anomalies du développement et syndromes malformatifs, FHU TRANSLAD et équipe GAD INSERM UMR1231, CHU Dijon-Bourgogne et Université de Bourgogne-Franche Comté, Dijon, France
  19. 19 Service de Génétique, EA3808, Université de Poitiers, CHU de Poitiers, Poitiers, France
  20. 20 Unité de Génétique Clinique, CHU de Rouen, Rouen, France
  21. 21 Service de Génétique Médicale, CHU-Nantes, Nantes, France
  22. 22 Laboratoire de Cytogénétique et de Biologie Cellulaire, CHU Pontchaillou, Rennes, France
  23. 23 Laboratoire de Cytogénétique, CHU de Rouen, Rouen, France
  24. 24 Laboratoire de Cytogénétique, CHU Strasbourg, Strasbourg, France
  25. 25 Service de Génétique Médicale, Hôpital Pellegrin, Université de Bordeaux, MRGM INSERM U1211, CHU Bordeaux, Bordeaux, France
  26. 26 Service de Génétique Clinique, Chromosomique et Moléculaire, CHU Hôpital Nord, Saint-Etienne, France
  27. 27 Laboratoire de Génétique Chromosomique, CH Général, Chambéry, France
  28. 28 Service de Cytogénétique, Hôpital Necker Enfants Malades, Paris, France
  29. 29 Département de Génétique; Centre de Référence Déficience Intellectuelle de Causes Rares, Groupe Hospitalier Pitié-Salpêtrière, APHP, Paris, France
  30. 30 Laboratoire de Génétique Chromosomique, Département de Génétique Médicale, AP-HM, Marseille, France
  31. 31 Service de Cytogénétique, CH Valence, Valence, France
  32. 32 Service de Cytogénétique Médicale, Hôpital Estaing, CHU Clermont-Ferrand, Clermont-Ferrand, France
  33. 33 CNRS, IGDR (Institut de Génétique et Développement de Rennes) UMR 6290, Université de Rennes, Rennes, France
  34. 34 Département de Génétique Médicale, Unité de Génétique Clinique, AP-HM, Marseille, France
  35. 35 Service de Génétique Médicale, Hôpital Estaing, CHU Clermont-Ferrand, Clermont-Ferrand, France
  36. 36 Equipe Génétique, Epigénétique et Thérapies de l’Infertilité, IAB, INSERM 1209, CNRS UMR5309, Grenoble, France
  37. 37 Service de Neurologie Pédiatrique, Hôpital Armand Trousseau, APHP, GHUEP, Paris, France
  1. Correspondence to Dr Caroline Schluth-Bolard, Service de Génétique, Centre de Référence des Anomalies du Développement, Centre Hospitalier Universitaire de Lyon, Bron cedex 69677, France; caroline.schluth-bolard{at}


Background Balanced chromosomal rearrangements associated with abnormal phenotype are rare events, but may be challenging for genetic counselling, since molecular characterisation of breakpoints is not performed routinely. We used next-generation sequencing to characterise breakpoints of balanced chromosomal rearrangements at the molecular level in patients with intellectual disability and/or congenital anomalies.

Methods Breakpoints were characterised by a paired-end low depth whole genome sequencing (WGS) strategy and validated by Sanger sequencing. Expression study of disrupted and neighbouring genes was performed by RT-qPCR from blood or lymphoblastoid cell line RNA.

Results Among the 55 patients included (41 reciprocal translocations, 4 inversions, 2 insertions and 8 complex chromosomal rearrangements), we were able to detect 89% of chromosomal rearrangements (49/55). Molecular signatures at the breakpoints suggested that DNA breaks arose randomly and that there was no major influence of repeated elements. Non-homologous end-joining appeared as the main mechanism of repair (55% of rearrangements). A diagnosis could be established in 22/49 patients (44.8%), 15 by gene disruption (KANSL1, FOXP1, SPRED1, TLK2, MBD5, DMD, AUTS2, MEIS2, MEF2C, NRXN1, NFIX, SYNGAP1, GHR, ZMIZ1) and 7 by position effect (DLX5, MEF2C, BCL11B, SATB2, ZMIZ1). In addition, 16 new candidate genes were identified. Systematic gene expression studies further supported these results. We also showed the contribution of topologically associated domain maps to WGS data interpretation.

Conclusion Paired-end WGS is a valid strategy and may be used for structural variation characterisation in a clinical setting.

  • whole genome sequencing
  • chromosomal rearrangements
  • intellectual disability
  • position effect
  • structural variation

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  • Contributors CS-B conceived the project, designed and coordinated the research, interpreted the data and wrote the paper. AA, FA, JA, SB, YC, PC, M-PC, CC, AC, FDem, FDev, MD-F, CD, SD-G, LF, A-MG, MH, BI, GJ-H, DL, AL, ML, GL, JL, AM-P, CMig, CMis, FM-P, SM, CP-R, SO, VP-F, LP, NP, MP, M-FP, FP, AP, MR, MasR, CS, MT, SV, AV, SW and PE provided patients phenotyping, collected clinical samples and enrolled the cohort. PC, BD, J-MD, BG, SJ, VK, CLC, JL, VM, MM-D, GN, JP, CR, VS, JP, RT, AT, A-CT, DS assisted design of the work and data interpretation. FD, NC, JM, LP conducted the experiments, analysed the data and contributed to the interpretation. P-AR-F, CB conducted bioinformatics analyses.

  • Funding This study was supported by the French Ministry of Health (DGOS) and the French National Agency for Research (ANR) (PRTS 2013 grant to CS-B, n° PRTSN1300001N).

  • Competing interests None declared.

  • Ethics approval This study was approved by the local ethics committee (CPP Lyon Sud-Est 06/04/2014).

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

  • Data sharing statement The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

  • Patient consent for publication Obtained.