Expanding the genetic and clinical spectrum of Tatton-Brown-Rahman syndrome in a series of 24 French patients
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Published:2024-06-27
Issue:9
Volume:61
Page:878-885
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ISSN:0022-2593
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Container-title:Journal of Medical Genetics
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language:en
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Short-container-title:J Med Genet
Author:
Thomas Hortense, Alix Tom, Renard Émeline, Renaud MathildeORCID, Wourms Justine, Zuily Stéphane, Leheup Bruno, Geneviève David, Dreumont Natacha, Schmitt Emmanuelle, Bronner Myriam, Muller Marc, Divoux Marion, Wandzel Marion, Ravel Jean-Marie, Dexheimer Mylène, Becker Aurélie, Roth Virginie, Willems Marjolaine, Coubes Christine, Vieville Gaëlle, Devillard Françoise, Schaefer Élise, Baer SarahORCID, Piton AmélieORCID, Gérard Bénédicte, Vincent Marie, Nizon Mathilde, Cogné BenjaminORCID, Ruaud Lyse, Couque Nathalie, Putoux Audrey, Edery Patrick, Lesca GaëtanORCID, Chatron Nicolas, Till Marianne, Faivre LaurenceORCID, Tran-Mau-Them Frédéric, Alessandri Jean-Luc, Lebrun Marine, Quélin Chloé, Odent Sylvie, Dubourg Christèle, David Véronique, Faoucher Marie, Mignot Cyril, Keren Boris, Pisan Élise, Afenjar Alexandra, Julia Sophie, Bieth Éric, Banneau Guillaume, Goldenberg Alice, Husson Thomas, Campion Dominique, Lecoquierre FrançoisORCID, Nicolas Gaël, Charbonnier Camille, De Saint Martin Anne, Naudion Sophie, Degoutin Manon, Rondeau Sophie, Michot Caroline, Cormier-Daire Valérie, Oussalah AbderrahimORCID, Pourié Carine, Lambert Laëtitia, Bonnet CélineORCID
Abstract
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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