The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants [version 1; referees: 3 approved]

Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) Research Study, Deciphering Developmental Disorders (DDD) Study, Katrina Tatton-Brown (Lead / Corresponding author), Anna Zachariou, Chey Loveday, Anthony Renwick, Shazia Mahamdallie, Lise Aksglaede, Diana Baralle, Daniela Barge-Schaapveld, Moira Blyth, Mieke Bouma, Jeroen Breckpot, Beau Crabb, Tabib Dabir, Valerie Cormier-Daire, Christine Fauth, Richard Fisher, Blanca Gener, David GoudieTessa Homfray, Matthew Hunter, Agnete Jorgensen, Sarina G Kant, Cathy Kirally-Borri, David Koolen, Ajith Kumar, Anatalia Labilloy, Melissa Lees, Carlo Marcelis, Catherine Mercer, Cyril Mignot, Kathryn Miller, Katherine Neas, Ruth Newbury-Ecob, Daniela T Pilz, Renata Posmyk, Carlos Prada, Keri Ramsey, Linda M Randolph, Angelo Selicorni, Deborah Shears, Mohnish Suri, I. Karen Temple, Peter Turnpenny, Lionel Val Maldergem, Vinod Varghese, Hermine E Veenstra-Knol, Naomi Yachelevich, Laura Yates, Nazneen Rahman

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Abstract

Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novo DNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight 32SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS

Original languageEnglish
Article number46
Pages (from-to)1-16
Number of pages16
JournalWellcome Open Research
Volume3
DOIs
Publication statusPublished - 23 Apr 2018

Keywords

  • DNMT3A
  • Intellectual disability
  • Overgrowth
  • Tatton-Brown-Rahman

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