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Am J Med Genet A. 2016 Dec;170(12):3069-3082. doi: 10.1002/ajmg.a.37940. Epub 2016 Sep 20.

Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations.

Author information

1
Department of Genetics, and INSERM U1211, University Hospital of Bordeaux, Bordeaux, France.
2
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
3
Department of Genetics, University Hospital Center, Bordeaux, France.
4
Unité de Génétique, Hospital Armand Trousseau-La Roche-Guyon, AP-HP, Paris, France.
5
Regional Genetics Unit, Children's Hospital of Eastern Ontario, Ottawa, Canada.
6
Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands.
7
Unité de Génétique Clinique, Hospital La Timone, AP-HM, Marseille, France.
8
Département de Génétique, Hospital Necker-Enfants Malades, AP-HP, Paris, France.
9
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
10
Center for Biomedical Research, Logrono-La Rioja, Spain.
11
Departement de Neuropédiatrie, Institut Jérôme Lejeune, Paris, France.
12
Serviço de Genética, Departamento de Pediatria, Hospital de Santa Maria, CHLN, Lisboa, Portugal.
13
Service de Génétique Médicale, CHU Estaing, Clermont-Ferrand, France.
14
Institute of Medical and Molecular Genetics, University Hospital La Paz, Madrid, Spain.
15
Genetics Clinic, Hospital de Sabadell, Corporació Sanitària Parc Taulí, Sabadell, Spain.
16
Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
17
Hospital de Cruces, Baracaldo, Spain.
18
Service de Génétique Médicale, Hospital Arnaud de Villeneuve, CHU Montpellier, Montpellier, France.
19
Service de Génétique, Hospital Clémenceau, CHU de Caen, Caen, France.
20
Department of Medical Genetics, University of Milan, Milan, Italy.
21
Unité de Génétique Clinique, Hospital Charles Nicolle, CHU Rouen, Rouen, France.
22
Department of Medical Genetics, Guy's and St Thomas Hospital, London, United Kingdom.
23
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom.
24
Laboratoire de Médecine Génétique, CHUQ Pavillon CHUL, Saint Foy, Canada.
25
PEDEGO Research Unit, and Medical Research Center Oulu, Department of Clinical Genetics, University of Oulu, Oulu University Hospital, Oulu, Finland.
26
Department of Molecular Medicine and Surgery, and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
27
Département de Pédiatrie et Génétique Médicale, Hospital Augustin Morvan, CHU Brest, Brest, France.
28
Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom.
29
Our Lady's Hospital for Sick Children, Crumlin, Ireland.
30
Unité de Génétique Médicale, CHI Poissy, Saint Germain en Laye, France.
31
Department of Paediatrics, Wroclaw Medical University, Wroclaw, Poland.
32
Division of Medical Genomics, Inova Translational Medical Institute, Falls Church.
33
Department of Genetics, Wroclaw Medical University, Wroclaw, Poland.
34
Department of Clinical Genetics and School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
35
Service de Génétique, Hospital Virgen de la Salud, Toledo, Spain.
36
Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
37
Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, United Kingdom.
38
Service de Génétique Clinique et Moléculaire, CHU Hôpital-Nord, Saint-Etienne, France.
39
Département de Génétique, CHU Robert Debré, AP-HP, Paris, France.
40
Service de Génétique Médicale, Hospital d'Arras, CHU de Lille, Arras, France.
41
Institute of Human Genetics, University Medical Centre, Mainz, Germany.
42
Department of Health Sciences, University of Milan, Milan, Italy.

Abstract

Rubinstein-Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8-10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype-phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia.

KEYWORDS:

EP300; Rubinstein-Taybi syndrome; genotype; phenotype; pre-eclampsia

PMID:
27648933
DOI:
10.1002/ajmg.a.37940
[Indexed for MEDLINE]

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