Wellcome Open Research (Apr 2018)
The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants [version 1; referees: 2 approved]
- Katrina Tatton-Brown,
- 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 Goudie,
- Tessa 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,
- Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) Research Study,
- Deciphering Developmental Disorders (DDD) Study,
- Nazneen Rahman
Affiliations
- Katrina Tatton-Brown
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
- Anna Zachariou
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
- Chey Loveday
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
- Anthony Renwick
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
- Shazia Mahamdallie
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
- Lise Aksglaede
- Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark
- Diana Baralle
- Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southhampton, UK
- Daniela Barge-Schaapveld
- Department of Clinical Genetics, Leiden University Medical Centre, Leiden, Netherlands
- Moira Blyth
- Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK
- Mieke Bouma
- Elver Intellectual Disability Centre, Nieuw Wehl, Netherlands
- Jeroen Breckpot
- Center for Human Genetics, University Hospitals and KU Leuven, Leuven, Belgium
- Beau Crabb
- Genetics Department, Children's Hospitals and Clinics of Minneapolis, Minneapolis, MN, USA
- Tabib Dabir
- Northern Ireland Regional Genetics Centre, Clinical Genetics Service, Belfast City Hospital, Belfast, UK
- Valerie Cormier-Daire
- INSERM UMR1163, IMAGINE Institute affiliate, Paris, France
- Christine Fauth
- Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria
- Richard Fisher
- Teesside Genetics Unit, The James Cook University Hospital, Middlesbrough, UK
- Blanca Gener
- Department of Genetics, Cruces University Hospital, Biocruces Health Research Institute, centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Basque Country, Spain
- David Goudie
- Department of Human Genetics, Ninewells Hospital and Medical School, Dundee, UK
- Tessa Homfray
- South West Thames Regional Genetics Service, St George’s University Hospitals NHS Foundation Trust, London, UK
- Matthew Hunter
- Monash Genetics, Monash Health, Melbourne, Australia
- Agnete Jorgensen
- Division of Child and Adolescent Health, Department of Medical Genetics, University Hospital of North Norway, Tromsø, Norway
- Sarina G. Kant
- Department of Clinical Genetics, Leiden University Medical Centre, Leiden, Netherlands
- Cathy Kirally-Borri
- Department of Health, Genetic Services of Western Australia, Subiaco, Australia
- David Koolen
- Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
- Ajith Kumar
- North East Thames Regional Genetics Service and Department of Clinical Genetics, Great Ormond Street Hospital, London, UK
- Anatalia Labilloy
- Department of Pediatrics, University of Cincinnati, College of Medicine, Division of Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Melissa Lees
- North East Thames Regional Genetics Service and Department of Clinical Genetics, Great Ormond Street Hospital, London, UK
- Carlo Marcelis
- Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
- Catherine Mercer
- Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southhampton, UK
- Cyril Mignot
- Département de Génétique and Centre de Référence Déficiences Intellectuelles de Causes Rares, Assistance Publique – Hôpitaux de Paris , Paris, France
- Kathryn Miller
- Albany Medical Center, New York, NY, USA
- Katherine Neas
- Genetic Health Service New Zealand, Wellington, New Zealand
- Ruth Newbury-Ecob
- University Hospitals Bristol NHS Trust/University of Bristol, Bristol, UK
- Daniela T. Pilz
- West of Scotland Clinical Genetics Service, Queen Elizabeth University Hospital,, Glasgow, UK
- Renata Posmyk
- Department of Clinical Genetics, Podlaskie Medical Center, Bialystok, Poland
- Carlos Prada
- Department of Pediatrics, University of Cincinnati, College of Medicine, Division of Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Keri Ramsey
- Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ, USA
- Linda M. Randolph
- Division of Medical Genetics, Children's Hospital Los Angeles, University of Southern California/ Keck School of Medicine, Los Angeles, CA, USA
- Angelo Selicorni
- UOC Pediatria ASST Laraina, Como, Italy
- Deborah Shears
- Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
- Mohnish Suri
- Nottingham Clinical Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, Nottingham, UK
- I. Karen Temple
- Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southhampton, UK
- Peter Turnpenny
- Peninsula Clinical Genetics, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK
- Lionel Val Maldergem
- Centre de Génétique Humaine and Integrative and Cognitive Neuroscience Research Unit EA481, Besançon, Besançon, France
- Vinod Varghese
- Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK
- Hermine E. Veenstra-Knol
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
- Naomi Yachelevich
- Clinical Genetics Services, New York University Hospitals Center, New York University, New York, NY, USA
- Laura Yates
- Teesside Genetics Unit, The James Cook University Hospital, Middlesbrough, UK
- Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) Research Study
- Deciphering Developmental Disorders (DDD) Study
- Nazneen Rahman
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
- DOI
- https://doi.org/10.12688/wellcomeopenres.14430.1
- Journal volume & issue
-
Vol. 3
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
