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

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

doi:10.12688/wellcomeopenres.14430.1

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

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

Authors

Katrina Tatton-Brown^{1

2

3}, Anna Zachariou¹, Chey Loveday¹, Anthony Renwick¹, Shazia Mahamdallie¹, Lise Aksglaede⁴, Diana Baralle⁵, Daniela Barge-Schaapveld⁶, Moira Blyth⁷, Mieke Bouma⁸, Jeroen Breckpot⁹, Beau Crabb¹⁰, Tabib Dabir¹¹, Valerie Cormier-Daire¹², Christine Fauth¹³, Richard Fisher¹⁴, Blanca Gener¹⁵, David Goudie¹⁶, Tessa Homfray^{2

3}, Matthew Hunter^{17

18}, Agnete Jorgensen¹⁹, Sarina G Kant⁶, Cathy Kirally-Borri²⁰, David Koolen²¹, Ajith Kumar²², Anatalia Labilloy^{23

24}, Melissa Lees²², Carlo Marcelis²¹, Catherine Mercer⁵, Cyril Mignot²⁵, Kathryn Miller²⁶, Katherine Neas²⁷, Ruth Newbury-Ecob²⁸, Daniela T Pilz²⁹, Renata Posmyk^{30

31}, Carlos Prada^{23

24}, Keri Ramsey³², Linda M Randolph³³, Angelo Selicorni³⁴, Deborah Shears³⁵, Mohnish Suri³⁶, I Karen Temple⁵, Peter Turnpenny³⁷, Lionel Val Maldergem³⁸, Vinod Varghese³⁹, Hermine E Veenstra-Knol⁴⁰, Naomi Yachelevich⁴¹, Laura Yates¹⁴; Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) Research Study; Deciphering Developmental Disorders (DDD) Study; Nazneen Rahman^{1

42}

Affiliations

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.

Abstract

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