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.

Academic Center for Epileptology Kempenhaeghe MUMC Maastricht The Netherlands

Big Data Institute Li Ka Shing Centre for Health Information and Discovery University of Oxford Oxford UK

Department of Cell Biology Biomedical Center of the Ludwig Maximilians Universität München Planegg Martinsried Germany

Department of Child Neurology Children's Hospital University of Helsinki and Helsinki University Hospital Helsinki Finland

Department of Clinical and Experimental Sciences School of Medicine University of Southampton Southampton UK

Department of Clinical Genetics and School for Oncology and Developmental Biology Maastricht University Medical Center Maastricht The Netherlands

Department of Clinical Genetics Laboratory Medicine Building Queen Elizabeth University Hospital Glasgow UK

Department of Clinical Genetics Royal Devon and Exeter NHS Trust Exeter UK

Department of Clinical Genetics School of Medicine and Medical Science Our Lady's Hospital University College Dublin Dublin Ireland

Department of Clinical Genetics University Hospitals Bristol Bristol UK

Department of Engineering Science Institute of Biomedical Engineering University of Oxford Oxford UK

Department of Genetics University Medical Center Groningen University of Groningen Groningen Netherlands

Department of Human Genetics and Genomic Medicine Faculty of Medicine University of Southampton Southampton UK

Department of Human Genetics Radboud University Medical Center Nijmegen The Netherlands

Department of Neurology and Pediatric Neurology Emma Children's Hospital Academic Medical Center Amsterdam The Netherlands

Department of Neurology Boston Children's Hospital Boston Massachusetts USA

Department of Neurology Maastricht University Medical Center Maastricht The Netherlands

Department of Neurology University of Melbourne Department of Paediatrics The Royal Children's Hospital Murdoch Children's Research Institute Melbourne Victoria Australia

Department of Ophthalmology Southampton General Hospital Southampton UK

Department of Orthopaedics Royal Children's Hospital Melbourne Victoria Australia

Department of Pediatric Neurology 2nd Faculty of Medicine Charles University Prague and University Hospital Motol Prague Czech Republic

Department of Pediatric Neurology Academic Medical Center Amsterdam The Netherlands

Department of Pediatric Neurology Children's Hospital of Pittsburgh of UPMC Pittsburgh Pennsylvania USA

Department of Pediatric Neurology Donders Institute for Brain Cognition and Behavior Radboud University Medical Center Nijmegen The Netherlands

Department of Pediatrics Máxima Medisch Centrum Veldhoven The Netherlands

Department of Pediatrics Rijnstate Hospital Arnhem The Netherlands

Department of Pediatrics Section of Neurology St Christopher's Hospital for Children Drexel University College of Medicine Philadelphia Pennsylvania USA

Departmentof Paediatrics Genetics Service KK Women's and Children's Hospital Singapore

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

Division of Medical Genetics Department of Pediatrics Schulich School of Medicine University of Western Ontario London Ontario Canada

Division of Neurology and Program for Genetics and Genome Biology Hospital for Sick Children Toronto Ontario Canada

Division of Pediatric Neurology Seattle Children's Hospital University of Washington Seattle Washington USA

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

Genome Institute of Singapore Singapore Singapore

Institute of Structural Biology Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

KK Research Laboratory KK Women's and Children's Hospital Singapore

National University Health Systems Cardiovascular Research Institute Singapore Singapore

North West Thames Regional Genetics Service London North West Healthcare NHS Trust London UK

Nuffield Department of Obstetrics and Gynaecology John Radcliffe Hospital Women's Centre University of Oxford Oxford UK

PURA Syndrome Foundation Tulsa Oklahoma USA

Research Programs Unit Molecular Neurology Biomedicum Helsinki University of Helsinki Helsinki Finland

Sanford Children's Hospital University of South Dakota Sioux Falls South Dakota USA

School for Mental Health and Neuroscience Maastricht University Maastricht The Netherlands

SW Thames Regional Genetics Service St George's University NHS Foundation Trust London UK

The Rina Mor Institute of Medical Genetics Holon Israel

Visual Geometry Group Department of Engineering Science University of Oxford Oxford UK

Wellcome Trust Sanger Institute Hinxton Cambridge UK

Wessex Clinical Genetics Service Princess Anne Hospital Southampton UK

West Midlands Regional Clinical Genetics Service Birmingham Women's NHS Foundation Trust Birmingham UK

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