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Original research
Expanding the genetic and clinical spectrum of Tatton-Brown-Rahman syndrome in a series of 24 French patients
  1. Hortense Thomas1,2,
  2. Tom Alix1,3,
  3. Émeline Renard3,4,
  4. Mathilde Renaud2,3,5,
  5. Justine Wourms2,
  6. Stéphane Zuily6,7,
  7. Bruno Leheup3,
  8. David Geneviève8,9,
  9. Natacha Dreumont3,
  10. Emmanuelle Schmitt10,
  11. Myriam Bronner1,
  12. Marc Muller1,
  13. Marion Divoux1,3,
  14. Marion Wandzel1,
  15. Jean-Marie Ravel1,3,
  16. Mylène Dexheimer1,
  17. Aurélie Becker1,
  18. Virginie Roth1,
  19. Marjolaine Willems8,
  20. Christine Coubes8,
  21. Gaëlle Vieville11,
  22. Françoise Devillard11,
  23. Élise Schaefer12,
  24. Sarah Baer12,
  25. Amélie Piton12,
  26. Bénédicte Gérard12,
  27. Marie Vincent13,14,
  28. Mathilde Nizon13,14,
  29. Benjamin Cogné13,14,
  30. Lyse Ruaud15,
  31. Nathalie Couque15,
  32. Audrey Putoux16,17,
  33. Patrick Edery16,17,
  34. Gaëtan Lesca16,17,
  35. Nicolas Chatron16,17,
  36. Marianne Till16,17,
  37. Laurence Faivre18,19,
  38. Frédéric Tran-Mau-Them19,20,
  39. Jean-Luc Alessandri21,
  40. Marine Lebrun22,
  41. Chloé Quélin23,
  42. Sylvie Odent23,
  43. Christèle Dubourg23,
  44. Véronique David23,
  45. Marie Faoucher23,
  46. Cyril Mignot24,
  47. Boris Keren24,
  48. Élise Pisan24,
  49. Alexandra Afenjar24,
  50. Sophie Julia25,
  51. Éric Bieth25,
  52. Guillaume Banneau25,
  53. Alice Goldenberg26,27,
  54. Thomas Husson27,28,29,
  55. Dominique Campion27,28,29,
  56. François Lecoquierre26,27,
  57. Gaël Nicolas26,27,
  58. Camille Charbonnier27,30,
  59. Anne De Saint Martin31,
  60. Sophie Naudion32,
  61. Manon Degoutin32,
  62. Sophie Rondeau33,34,
  63. Caroline Michot33,34,
  64. Valérie Cormier-Daire33,34,
  65. Abderrahim Oussalah3,35,
  66. Carine Pourié3,
  67. Laëtitia Lambert2,3,
  68. Céline Bonnet1,3
  1. 1Laboratoire de Génétique, CHRU de Nancy, Vandœuvre-lès-Nancy, France
  2. 2Service de Génétique Clinique, CHRU de Nancy, Nancy, France
  3. 3INSERM NGERE U1256, Université de Lorraine, Vandœuvre-lès-Nancy, France
  4. 4Endocrinologie pédiatrique, CHRU de Nancy, Vandœuvre-lès-Nancy, France
  5. 5Service de Neurologie, CHRU de Nancy, Nancy, France
  6. 6Médecine Vasculaire, CHRU de Nancy, Vandœuvre-lès-Nancy, France
  7. 7UMR_S 916 DCAC, INSERM, Vandœuvre-lès-Nancy, France
  8. 8Centre de référence anomalies du développement et syndromes malformatifs, Département de Génétique Medicale, Maladies Rares et Médecine Personnalisée, Hôpital Arnaud de Villeneuve, CHU de Montpellier, Montpellier, France
  9. 9Inserm U1183, Université Montpellier 1, Faculté de Médecine Montpellier-Nîmes, Montpellier, France
  10. 10Neuroradiologie, CHRU de Nancy, Vandœuvre-lès-Nancy, France
  11. 11Département de Génétique et Procréation, Hôpital Couple Enfant, CHU Grenoble Alpes, Grenoble, France
  12. 12Service de Génétique médicale, Institut de Génétique Médicale d’Alsace, CHU de Strasbourg, Strasbourg, France
  13. 13Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France
  14. 14CNRS, INSERM, Institut du thorax, Nantes Université, Nantes, France
  15. 15Département de Génétique, Hôpital Robert Debré, APHP Nord, Paris, France
  16. 16Service de Génétique, Hospices Civils de Lyon, Groupe Hospitalier Est, Bron, France
  17. 17CNRS UMR5310, INSERM U1217, Institut NeuroMyoGene PNMG, Université Claude Bernard Lyon 1, Lyon, France
  18. 18Centre de référence anomalies du développement et syndromes malformatifs et Centre de référence Déficiences Intellectuelles de causes rares, FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France
  19. 19UMR1231 GAD, Inserm, Université Bourgogne Franche-Comté, Dijon, France
  20. 20Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France
  21. 21Service de génétique médicale, CHU de La Réunion, Hôpital Félix Guyon, Bellepierre, Saint-Denis, Réunion
  22. 22Département de Génétique, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France
  23. 23Département de génétique moléculaire et génomique, CHU Rennes, Rennes, France
  24. 24Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, APHP Sorbonne Université, Paris, France
  25. 25Département de Génétique médicale, CHU Toulouse, Toulouse, France
  26. 26Department of Genetics and Reference Center for Developmental Disorders, CHU de Rouen, Rouen, France
  27. 27Inserm U1245, Université de Rouen Normandie, Rouen, France
  28. 28Department of Psychiatry, CHU de Rouen, Rouen, France
  29. 29Department of Research, Centre hospitalier du Rouvray, Sotteville-Lès-Rouen, France
  30. 30Department of Biotatistics, CHU de Rouen, Rouen, France
  31. 31Centre de Référence des épilepsies Rares, Hopitaux universitaires de Strasbourg, Strasbourg, France
  32. 32Service de Génétique Médicale, Centre Hospitalier Universitaire de Bordeaux, Groupe hospitalier Pellegrin, Bordeaux, France
  33. 33Centre de référence des maladies osseuses constitutionnelles, Necker-Enfants Malades Hospitals, Paris, France
  34. 34INSERM UMR 1163, Imagine Institute, Paris, France
  35. 35Department of Molecular Medicine, Division of Biochemistry, Molecular Biology, and Nutrition, CHRU de Nancy, Nancy, France
  1. Correspondence to Dr Céline Bonnet, Laboratoire de génétique, CHRU de Nancy, Nancy 54000, France; ce.bonnet{at}


Background Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as DNA methyltransferase 3 alpha (DNMT3A)-overgrowth syndrome (DOS), was first described by Tatton-Brown in 2014. This syndrome is characterised by overgrowth, intellectual disability and distinctive facial features and is the consequence of germline loss-of-function variants in DNMT3A, which encodes a DNA methyltransferase involved in epigenetic regulation. Somatic variants of DNMT3A are frequently observed in haematological malignancies, including acute myeloid leukaemia (AML). To date, 100 individuals with TBRS with de novo germline variants have been described. We aimed to further characterise this disorder clinically and at the molecular level in a nationwide series of 24 French patients and to investigate the correlation between the severity of intellectual disability and the type of variant.

Methods We collected genetic and medical information from 24 individuals with TBRS using a questionnaire released through the French National AnDDI-Rares Network.

Results Here, we describe the first nationwide French cohort of 24 individuals with germline likely pathogenic/pathogenic variants in DNMT3A, including 17 novel variants. We confirmed that the main phenotypic features were intellectual disability (100% of individuals), distinctive facial features (96%) and overgrowth (87%). We highlighted novel clinical features, such as hypertrichosis, and further described the neurological features and EEG results.

Conclusion This study of a nationwide cohort of individuals with TBRS confirms previously published data and provides additional information and clarifies clinical features to facilitate diagnosis and improve care. This study adds value to the growing body of knowledge on TBRS and broadens its clinical and molecular spectrum.

  • genetic diseases, inborn
  • exome sequencing
  • genetics, medical
  • loss of function mutation
  • mental disorders

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study.

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Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study.

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  • LL and CB are joint senior authors.

  • X @NicoChatron

  • HT and TA contributed equally.

  • LL and CB contributed equally.

  • Contributors CB is the guarantor. LL, MR and CB conceptualised and designed the study. CB collected the samples. LL, MR, ER, JW, SZ, BL, DG, MWi, CC, ES, SB, MV, MN, LR, EP, PE, LF, J-LA, ML, CQ, SO, CM, AA, SJ, AG, ADSM, SN, MDe, CM and VC-D clinically characterised the individuals. TA, CP, ND, JMR, MWa, MB, AB, VR, MM, MDi, GV, AP, BG, BC, GL, NCh, MT, FT-M-T, VD, MF, NCo, BK, SR, EB, GB, TH, AO and CB performed the genetic studies and data analysis and interpretation. TH, DC, FL, GN and CC generated DNA methylation data from patient 13 and interpreted the DNMT3A episignature. HT collected the clinical data. TA and CB collected the molecular data. HT wrote the first draft of the manuscript. TA, ER, JMR, LL and CB revised the manuscript. CB supervised the project and edited the manuscript. All the authors critically revised and approved the final manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Disclaimer The sponsor was CHRU de Nancy (Direction de la Recherche et de l’Innovation).

  • Competing interests None declared.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.