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Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability
  1. Martin Chevarin1,
  2. Yannis Duffourd1,2,
  3. Rebecca A. Barnard3,
  4. Sébastien Moutton1,4,5,
  5. François Lecoquierre1,
  6. Fatma Daoud1,
  7. Paul Kuentz1,2,
  8. Caroline Cabret1,
  9. Julien Thevenon1,4,
  10. Elodie Gautier2,
  11. Patrick Callier1,2,
  12. Judith St-Onge1,
  13. Thibaud Jouan1,
  14. Didier Lacombe5,
  15. Marie Ange Delrue5,
  16. Cyril Goizet5,
  17. Fanny Morice-Picard5,
  18. Julien Van-Gils5,
  19. Arnold Munnich6,
  20. Stanislas Lyonnet6,
  21. Valérie Cormier-Daire6,
  22. Geneviève Baujat6,
  23. Muriel Holder7,
  24. Florence Petit7,
  25. Bruno Leheup8,
  26. Sylvie Odent9,
  27. Pierre-Simon Jouk10,
  28. Gipsy Lopez10,
  29. David Geneviève11,
  30. Patrick Collignon12,
  31. Dominique Martin-Coignard13,
  32. Aurélia Jacquette14,
  33. Laurence Perrin15,
  34. Audrey Putoux16,
  35. Elisabeth Sarrazin17,
  36. Khadija Amarof17,
  37. Isabelle Missotte18,
  38. Christine Coubes11,
  39. Sujatha Jagadeesh19,
  40. Elisabetta Lapi20,
  41. Florence Demurger21,
  42. Alice Goldenberg22,
  43. Martine Doco-Fenzy23,
  44. Cyril Mignot14,
  45. Delphine Héron14,
  46. Nolwenn Jean-Marçais2,
  47. Alice Masurel4,
  48. Salima El Chehadeh4,
  49. Nathalie Marle1,2,
  50. Frédéric Huet2,24,
  51. Christine Binquet25,
  52. Gwenaëlle Collod-Beroud26,
  53. Pauline Arnaud27,
  54. Nadine Hanna27,
  55. Catherine Boileau27,
  56. Guillaume Jondeau27,
  57. Robert Olaso28,
  58. Doris Lechner28,
  59. Charlotte Poe1,
  60. Mirna Assoum1,
  61. Virginie Carmignac1,
  62. Laurence Duplomb1,
  63. Frédéric Tran Mau-Them1,
  64. Christophe Philippe1,
  65. Antonio Vitobello1,
  66. Ange-Line Bruel1,
  67. Anne Boland28,
  68. Jean-François Deleuze28,
  69. Christel Thauvin-Robinet1,2,29,
  70. Jean-Baptiste Rivière1,2,
  71. Brian J O'Roak3,
  72. Laurence Faivre1,2,4,29
  1. 1 INSERM, U1231, Génétique des Anomalies du Développement, Université de Bourgogne Franche-Comté, UMR Lipides, Nutrition, Dijon, France
  2. 2 FHU TRANSLAD, CHU Dijon, Dijon, France
  3. 3 Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, Oregon, USA
  4. 4 Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l’interrégion Est, Centre Hospitalier Universitaire Dijon, Dijon, France
  5. 5 Centre de Référence Anomalies du Développement et Syndromes Malformatifs Sud-Ouest, Centre Hospitalier Universitaire Bordeaux, Bordeaux, France
  6. 6 IHU Imagine, Département de Génétique, APHP, Hôpital Necker Enfants Malades, Paris, France
  7. 7 Centre de Référence Anomalies du Développement et Syndromes Malformatifs Nord, Centre Hospitalier Universitaire Lille, Lille, France
  8. 8 Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l’interrégion Ouest, Centre Hospitalier Universitaire Nancy, Nancy, France
  9. 9 Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l’interrégion Est, Centre Hospitalier Universitaire Rennes, Rennes, France
  10. 10 Centre de Référence Anomalies du Développement et Syndromes Malformatifs Centre Est, Centre Hospitalier Universitaire Grenoble, Grenoble, France
  11. 11 Centre de Référence Anomalies du Développement et Syndromes Malformatifs Sud-Languedoc Roussillon, Centre Hospitalier Universitaire Montpellier, Montpellier, France
  12. 12 Centre de Compétence Anomalies du Développement et Syndromes Malformatifs Sud-Est, CHI de Toulon – La Seyne-sur-Mer, France
  13. 13 Centre de compétence Anomalies du Développement et Syndromes Malformatifs, CH Le Mans, Le Mans, France
  14. 14 Département de Génétique et Centre de Référence Déficiences intellectuelles de causes rares, APHP, La Pitié Salpêtrière, Paris, France
  15. 15 Centre de Référence Anomalies du Développement et Syndromes Malformatifs Ile de France, APHP, Hôpital Robert Debré, Paris, France
  16. 16 Centre de Référence Anomalies du Développement et Syndromes Malformatifs Centre Est, Hospices Civils de Lyon, Lyon, France
  17. 17 Centre de Référence Caribéen des Maladies Rares Neurologiques et Neuromusculaires, CHU de Fort de France, Hôpital Pierre Zobda-Quitman, La Martinique, France
  18. 18 Service de Pédiatrie, Centre Hospitalier Territorial, Nouvelle Calédonie, France
  19. 19 Geneomm Medical Centre, Mediscan, Chennai, India
  20. 20 Genetica Medica, Azienda Ospedaliera Universitaria Anna Meyer, Firenze, Italia
  21. 21 Service de Pédiatrie Génétique, CH de Vannes, Vannes, France
  22. 22 Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU Rouen, Rouen, France
  23. 23 EA3801, Centre de Référence Anomalies du Développement et Syndromes Malformatifs et service de génétique, CHU Reims et UFR de médecine de Reims, Reims, France
  24. 24 Service de Pédiatrie 1, Centre Hospitalier Universitaire Dijon, Dijon, France
  25. 25 Centre d’Investigation Clinique – Epidémiologie Clinique, Centre Hospitalier Universitaire Dijon, Dijon, France
  26. 26 Aix Marseille Univ, INSERM, Marseille Medical Genetics (MMG), Marseille, France
  27. 27 Centre de référence syndromes de Marfan et syndromes apparentés, APHP, Hôpital Bichat, Paris, France
  28. 28 Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France
  29. 29 Centre de Référence Déficience intellectuelle, Centre Hospitalier Universitaire Dijon, Dijon, France
  1. Correspondence to Professor Laurence Faivre, Centre de Génétique, Hôpital d'Enfants, Dijon 21079, France; laurence.faivre{at}chu-dijon.fr

Abstract

Purpose Marfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan–Fryns syndrome explain no more than 20% of subjects.

Methods To further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic.

Results We identified eight genes with de novo variants (DNVs) in at least two unrelated individuals (ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205 and ZEB2). Using simulation models, we showed that five genes (DLG4, NFIX, EHMT1, ZEB2 and ATP1A1) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including NSD1 and NFIX, which are known to be mutated in overgrowth syndromes.

Conclusion We demonstrated that DNVs were enriched in chromatin remodelling (p=2×10−4) and genes regulated by the fragile X mental retardation protein (p=3×10−8), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.

  • marfanoid habitus
  • intellectual deficiency
  • exome sequencing
  • chromatin remodeling
  • de novo variants
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Footnotes

  • MC, YD, RAB, J-BR, BJO and LF contributed equally.

  • Contributors LF and JBR designed the study. MC, FD, CC, JSO, TJ, RO, DL, CP, AB, JFD performed the genetics experiments. FL, PK, JT, PC, GCB, MA, VC, LD, FTMT, CP, AV, ALB analysed the genetic results. YD performed the bioinformatics experiments. RAB and BOR performed the statistical experiments. SM, DL, MAD, CG, FMP, JVG, AM, SL, VCD, GB, MH, FP, BL, SO, PSK, GL, DG, PC, DMC, AJ, LP, AP, ES, KA, IM, CC, SJ, EL, FD, AG, MDF, CM, DH, NJM, AM, SEC, NM, FH, PA, NH, CB, GJ recruited and evaluated the study subjects. EG and CB were in charge of the administrative follow-up of the study. LF, CTR, JBR, BOR supervised the study. LF, BOR, MC, YD, and RAB wrote the manuscript. All authors revised the manuscript.

  • Funding This work was funded by the French Ministry of Health (PHRC national 2008/2008-A00515-50), the Regional Council of Burgundy / Dijon University hospital (PARI 2012) and the European Union through the PO FEDER-FSE Bourgogne 2014/2020. B.J.O. is a Klingenstein-Simons (Esther A. & Joseph Klingenstein Fund, Simons Foundation) and Sloan Research (Alfred P. Sloan Foundation) Fellow in Neurosciences.

  • Competing interests None declared.

  • Patient consent for publication Not required.

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

  • Data availability statement Data are available in a public, open access repository.

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