Article Dans Une Revue Journal of Medical Genetics Année : 2024

Expanding the genetic and clinical spectrum of Tatton-Brown-Rahman syndrome in a series of 24 French patients

Hortense Thomas (1) , Tom Alix (1, 2) , Émeline Renard (2, 1) , Mathilde Renaud (3, 2) , Justine Wourms (3) , Stéphane Zuily (4, 1) , Bruno Leheup (2) , David Geneviève (5, 6) , Natacha Dreumont (2) , Emmanuelle Schmitt (7, 8) , Myriam Bronner (9) , Marc Muller (3) , Marion Divoux (10, 3) , Marion Wandzel (3) , Jean-Marie Ravel (2, 1) , Mylène Dexheimer (3) , Aurélie Becker (3) , Virginie Roth (3) , Marjolaine Willems (11, 5) , Christine Coubes (5) , Gaëlle Vieville (12, 13) , Françoise Devillard (12, 13) , Élise Schaefer (14) , Sarah Baer (14) , Amélie Piton (14) , Bénédicte Gérard (14) , Marie Vincent (15, 16) , Mathilde Nizon (15, 16) , Benjamin Cogné (15, 16) , Lyse Ruaud (17) , Nathalie Couque (17) , Audrey Putoux (18, 19) , Patrick Edery (18, 19) , Gaëtan Lesca (18, 19) , Nicolas Chatron (18, 19) , Marianne Till (18, 19) , Laurence Faivre (20, 21) , Frédéric Tran-Mau-Them (21, 20) , Jean-Luc Alessandri (22) , Marine Lebrun (23) , Chloé Quélin (24) , Sylvie Odent (25, 24) , Christèle Dubourg (25, 24) , Véronique David (25, 24) , Marie Faoucher (25, 24) , Cyril Mignot (26) , Boris Keren (26) , Élise Pisan (26) , Alexandra Afenjar (26) , Sophie Julia (27) , Éric Bieth (27) , Guillaume Banneau (27) , Alice Goldenberg (28, 29) , Thomas Husson (28, 29) , Dominique Campion (28, 29) , François Lecoquierre (28, 29) , Gaël Nicolas (28, 29) , Camille Charbonnier (28, 29) , Anne de Saint Martin (30) , Sophie Naudion (31) , Manon Degoutin (31) , Sophie Rondeau (32, 33) , Caroline Michot (32, 33) , Valérie Cormier-Daire (32, 33) , Abderrahim Oussalah (2, 34) , Carine Pourié (2) , Laëtitia Lambert (2, 9) , Céline Bonnet (2, 1)
1 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
2 NGERE - Nutrition-Génétique et Exposition aux Risques Environnementaux
3 Service de Génétique [CHRU Nancy]
4 DCAC - Défaillance Cardiovasculaire Aiguë et Chronique
5 Département de génétique médicale, maladies rares et médecine personnalisée [CHU Montpellier]
6 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
7 BIOC - Laboratoire de Biologie Structurale de la Cellule
8 Département de neuroradiologie diagnostique et thérapeutique [CHRU Nancy]
9 Service de Génétique Clinique [CHRU Nancy]
10 UL - Université de Lorraine
11 INM - Institut des Neurosciences de Montpellier
12 Pôle Couple-Enfant, Département de Génétique et Procréation
13 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
14 IGMA - Institut de génétique médicale d’Alsace
15 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
16 Institut du Thorax [Nantes]
17 Département de génétique [Robert Debré]
18 HCL - Hospices Civils de Lyon
19 INMG - Institut NeuroMyoGène
20 FHU TRANSLAD (CHU de Dijon)
21 GAD - Génétique des anomalies du développement (CTM UMR 1231)
22 Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion]
23 CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
24 Service de Génétique moléculaire et Génomique [CHU Rennes]
25 IGDR - Institut de Génétique et Développement de Rennes
26 CHU Pitié-Salpêtrière [AP-HP]
27 Service Génétique Médicale [CHU Toulouse]
28 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
29 CHU Rouen
30 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]
31 CHU Bordeaux - Centre Hospitalier Universitaire de Bordeaux
32 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
33 Hôpital Necker - Enfants Malades [AP-HP]
34 Biochimie – Biologie moléculaire et Nutrition [CHRU Nancy]
Sarah Baer
Gaëtan Lesca

Résumé

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.
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hal-04811418 , version 1 (19-12-2024)

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Hortense Thomas, Tom Alix, Émeline Renard, Mathilde Renaud, Justine Wourms, et al.. Expanding the genetic and clinical spectrum of Tatton-Brown-Rahman syndrome in a series of 24 French patients. Journal of Medical Genetics, 2024, 61 (9), pp.878-885. ⟨10.1136/jmg-2024-110031⟩. ⟨hal-04811418⟩
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