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

doi:10.12688/wellcomeopenres.14430.1

. 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

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.

PMID: 29900417
PMCID: PMC5964628
DOI: 10.12688/wellcomeopenres.14430.1

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

Katrina Tatton-Brown et al. Wellcome Open Res. 2018.

. 2018 Apr 23:3:46.

doi: 10.12688/wellcomeopenres.14430.1. eCollection 2018.

Authors

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.

PMID: 29900417
PMCID: PMC5964628
DOI: 10.12688/wellcomeopenres.14430.1

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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Conflict of interest statement

No competing interests were disclosed.

Figures

Figure 1.. DNMT3A and the positions and types of variants with protein truncating variants shown below the protein (black and red lollipops) and missense variants and inframe deletions (yellow and blue lollipops) shown above the protein.
Whole gene deletions and the splice site variant are not shown on this figure. The three DNMT3A domains are shaded in grey: the proline-tryptophan-tryptophan-proline (PWWP) domain, the ATRX-Dnmt3-Dnmt3L (ADD) domain and the Methyltransferase (MTase) domain.

**Figure 2.. Graph showing the range of intellectual disability in TBRS.**

**Figure 3.**
Growth profile in individuals with TBRS a) height, b) head circumference and c) weight. The blue line represents the mean.

**Figure 4.**
a) The facial appearance of children and adults with TBRS; b) the evolving facial appearance in four individuals with TBRS; and c) the characteristic short, widely spaced toes seen in TBRS.

See this image and copyright information in PMC

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References

1. Tatton-Brown K, Seal S, Ruark E, et al. : Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat Genet. 2014;46(4):385–388. 10.1038/ng.2917 - DOI - PMC - PubMed
1. Tatton-Brown K, Loveday C, Yost S, et al. : Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability. Am J Hum Genet. 2017;100(5):725–736. 10.1016/j.ajhg.2017.03.010 - DOI - PMC - PubMed
1. Okamoto N, Toribe Y, Shimojima K, et al. : Tatton-Brown-Rahman syndrome due to 2p23 microdeletion. Am J Med Genet A. 2016;170A(5):1339–1342. 10.1002/ajmg.a.37588 - DOI - PubMed
1. Tlemsani C, Luscan A, Leulliot N, et al. : SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort. J Med Genet. 2016;53(11):743–751, pii: jmedgenet-2015-103638. 10.1136/jmedgenet-2015-103638 - DOI - PubMed
1. Xin B, Cruz Marino T, Szekely J, et al. : Novel DNMT3A germline mutations are associated with inherited Tatton-Brown-Rahman syndrome. Clin Genet. 2017;91(4):623–628. 10.1111/cge.12878 - DOI - PubMed

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[1] Tatton-Brown K, Seal S, Ruark E, et al. : Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat Genet. 2014;46(4):385–388. 10.1038/ng.2917 - DOI - PMC - PubMed

[2] Tatton-Brown K, Seal S, Ruark E, et al. : Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat Genet. 2014;46(4):385–388. 10.1038/ng.2917 - DOI - PMC - PubMed

[3] Tatton-Brown K, Loveday C, Yost S, et al. : Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability. Am J Hum Genet. 2017;100(5):725–736. 10.1016/j.ajhg.2017.03.010 - DOI - PMC - PubMed

[4] Tatton-Brown K, Loveday C, Yost S, et al. : Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability. Am J Hum Genet. 2017;100(5):725–736. 10.1016/j.ajhg.2017.03.010 - DOI - PMC - PubMed

[5] Okamoto N, Toribe Y, Shimojima K, et al. : Tatton-Brown-Rahman syndrome due to 2p23 microdeletion. Am J Med Genet A. 2016;170A(5):1339–1342. 10.1002/ajmg.a.37588 - DOI - PubMed

[6] Okamoto N, Toribe Y, Shimojima K, et al. : Tatton-Brown-Rahman syndrome due to 2p23 microdeletion. Am J Med Genet A. 2016;170A(5):1339–1342. 10.1002/ajmg.a.37588 - DOI - PubMed

[7] Tlemsani C, Luscan A, Leulliot N, et al. : SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort. J Med Genet. 2016;53(11):743–751, pii: jmedgenet-2015-103638. 10.1136/jmedgenet-2015-103638 - DOI - PubMed

[8] Tlemsani C, Luscan A, Leulliot N, et al. : SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort. J Med Genet. 2016;53(11):743–751, pii: jmedgenet-2015-103638. 10.1136/jmedgenet-2015-103638 - DOI - PubMed

[9] Xin B, Cruz Marino T, Szekely J, et al. : Novel DNMT3A germline mutations are associated with inherited Tatton-Brown-Rahman syndrome. Clin Genet. 2017;91(4):623–628. 10.1111/cge.12878 - DOI - PubMed

[10] Xin B, Cruz Marino T, Szekely J, et al. : Novel DNMT3A germline mutations are associated with inherited Tatton-Brown-Rahman syndrome. Clin Genet. 2017;91(4):623–628. 10.1111/cge.12878 - DOI - PubMed

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

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

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