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J Med Genet. 2018 Feb;55(2):104-113. doi: 10.1136/jmedgenet-2017-104946. Epub 2017 Nov 2.

PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature.

Author information

1
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
2
Institute of Structural Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
3
Visual Geometry Group, Department of Engineering Science, University of Oxford, Oxford, UK.
4
Department of Ophthalmology, Southampton General Hospital, Southampton, UK.
5
Department of Clinical and Experimental Sciences, School of Medicine, University of Southampton, Southampton, UK.
6
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
7
Department of Clinical Genetics and School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, The Netherlands.
8
Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.
9
School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
10
Academic Center for Epileptology, Kempenhaeghe/MUMC, Maastricht, The Netherlands.
11
Department of Pediatric Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
12
Department of Pediatrics, Rijnstate Hospital, Arnhem, The Netherlands.
13
Department of Pediatrics, Máxima Medisch Centrum, Veldhoven, The Netherlands.
14
Department of Pediatric Neurology, Academic Medical Center, Amsterdam, The Netherlands.
15
Department of Neurology and Pediatric Neurology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands.
16
SW Thames Regional Genetics Service, St. George's University NHS Foundation Trust, London, UK.
17
Department of Clinical Genetics, Laboratory Medicine Building, Queen Elizabeth University Hospital, Glasgow, UK.
18
Division of Evolution and Genomic Sciences, School of Biological Sciences, Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.
19
West Midlands Regional Clinical Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham, UK.
20
KK Research Laboratory, KK Women's and Children's Hospital, Singapore.
21
National University Health Systems, Cardiovascular Research Institute, Singapore, Singapore.
22
Genome Institute of Singapore, Singapore, Singapore.
23
Departmentof Paediatrics, Genetics Service, KK Women's and Children's Hospital, Singapore.
24
Department of Clinical Genetics, Royal Devon and Exeter NHS Trust, Exeter, UK.
25
Department of Clinical Genetics, School of Medicine and Medical Science, Our Lady's Hospital, University College Dublin, Dublin, Ireland.
26
Department of Child Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
27
Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
28
Department of Pediatric Neurology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.
29
Division of Pediatric Neurology, Seattle Children's Hospital/University of Washington, Seattle, Washington, USA.
30
Department of Pediatrics, Section of Neurology, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
31
Division of Neurology and Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
32
The Rina Mor Institute of Medical Genetics, Holon, Israel.
33
Department of Pediatric Neurology, Second Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
34
Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.
35
Sanford Children's Hospital, University of South Dakota, Sioux Falls, South Dakota, USA.
36
Faculty of Medical and Human Sciences, Institute of Evolution, Systems and Genomics, University of Manchester, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
37
Department of Clinical Genetics, University Hospitals Bristol, Bristol, UK.
38
PURA Syndrome Foundation, Tulsa, Oklahoma, USA.
39
North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, London, UK.
40
Division of Medical Genetics, Department of Pediatrics, Schulich School of Medicine, University of Western Ontario, London, Ontario, Canada.
41
Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
42
Department of Orthopaedics, Royal Children's Hospital, Melbourne, Victoria, Australia.
43
Department of Neurology, University of Melbourne Department of Paediatrics, The Royal Children's Hospital, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
44
Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
45
Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital Women's Centre, University of Oxford, Oxford, UK.
46
Department of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Oxford, UK.
47
Department of Cell Biology, Biomedical Center of the Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany.
48
Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
49
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.

Abstract

BACKGROUND:

De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia.

OBJECTIVES:

To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations.

METHODS:

Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes.

RESULTS:

We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes.

CONCLUSION:

We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.

KEYWORDS:

PURA syndrome; epilepsy and seizures; hypotonia; intellectual disability; neonatal problems

PMID:
29097605
PMCID:
PMC5800346
DOI:
10.1136/jmedgenet-2017-104946
[Indexed for MEDLINE]
Free PMC Article

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