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Wellcome Open Res. 2018 Apr 23;3:46. doi: 10.12688/wellcomeopenres.14430.1. eCollection 2018.

The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants.

Author information

1
Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
2
South West Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust, London, UK.
3
St George's University of London, London, UK.
4
Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark.
5
Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southhampton, UK.
6
Department of Clinical Genetics, Leiden University Medical Centre, Leiden, Netherlands.
7
Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK.
8
Elver Intellectual Disability Centre, Nieuw Wehl, Netherlands.
9
Center for Human Genetics, University Hospitals and KU Leuven, Leuven, Belgium.
10
Genetics Department, Children's Hospitals and Clinics of Minneapolis, Minneapolis, MN, USA.
11
Northern Ireland Regional Genetics Centre, Clinical Genetics Service, Belfast City Hospital, Belfast, UK.
12
INSERM UMR1163, IMAGINE Institute affiliate, Paris, France.
13
Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
14
Teesside Genetics Unit, The James Cook University Hospital, Middlesbrough, UK.
15
Department of Genetics, Cruces University Hospital, Biocruces Health Research Institute, centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Basque Country, Spain.
16
Department of Human Genetics, Ninewells Hospital and Medical School, Dundee, UK.
17
Monash Genetics, Monash Health, Melbourne, Australia.
18
Department of Paediatrics, Monash University, Melbourne, Australia.
19
Division of Child and Adolescent Health, Department of Medical Genetics, University Hospital of North Norway, Tromsø, Norway.
20
Department of Health, Genetic Services of Western Australia, Subiaco, Australia.
21
Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands.
22
North East Thames Regional Genetics Service and Department of Clinical Genetics, Great Ormond Street Hospital, London, UK.
23
Department of Pediatrics, University of Cincinnati, College of Medicine, Division of Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
24
Hospital Internacional de Colombia, Floridablanca, Colombia.
25
Département de Génétique and Centre de Référence Déficiences Intellectuelles de Causes Rares, Assistance Publique - Hôpitaux de Paris , Paris, France.
26
Albany Medical Center, New York, NY, USA.
27
Genetic Health Service New Zealand, Wellington, New Zealand.
28
University Hospitals Bristol NHS Trust/University of Bristol, Bristol, UK.
29
West of Scotland Clinical Genetics Service, Queen Elizabeth University Hospital,, Glasgow, UK.
30
Department of Clinical Genetics, Podlaskie Medical Center, Bialystok, Poland.
31
Department of Perinatology and Obstetrics, Medical University in Bialystok, Bialystok, Poland.
32
Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ, USA.
33
Division of Medical Genetics, Children's Hospital Los Angeles, University of Southern California/ Keck School of Medicine, Los Angeles, CA, USA.
34
UOC Pediatria ASST Laraina, Como, Italy.
35
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
36
Nottingham Clinical Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, Nottingham, UK.
37
Peninsula Clinical Genetics, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK.
38
Centre de Génétique Humaine and Integrative and Cognitive Neuroscience Research Unit EA481, Besançon, Besançon, France.
39
Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
40
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
41
Clinical Genetics Services, New York University Hospitals Center, New York University, New York, NY, USA.
42
Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, UK.

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 novoDNMT3A 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.

KEYWORDS:

DNMT3A; Tatton-Brown-Rahman; intellectual disability; overgrowth

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