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Original Article
PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature
  1. Margot R F Reijnders1,
  2. Robert Janowski2,
  3. Mohsan Alvi3,
  4. Jay E Self4,5,
  5. Ton J van Essen6,
  6. Maaike Vreeburg7,
  7. Rob P W Rouhl8,9,10,
  8. Servi J C Stevens7,
  9. Alexander P A Stegmann7,
  10. Jolanda Schieving11,
  11. Rolph Pfundt1,
  12. Katinke van Dijk12,
  13. Eric Smeets7,
  14. Connie T R M Stumpel7,
  15. Levinus A Bok13,
  16. Jan Maarten Cobben14,
  17. Marc Engelen15,
  18. Sahar Mansour16,
  19. Margo Whiteford17,
  20. Kate E Chandler18,
  21. Sofia Douzgou18,
  22. Nicola S Cooper19,
  23. Ene-Choo Tan20,
  24. Roger Foo21,22,
  25. Angeline H M Lai23,
  26. Julia Rankin24,
  27. Andrew Green25,
  28. Tuula Lönnqvist26,
  29. Pirjo Isohanni26,27,
  30. Shelley Williams28,
  31. Ilene Ruhoy29,
  32. Karen S Carvalho30,
  33. James J Dowling31,
  34. Dorit L Lev32,
  35. Katalin Sterbova33,
  36. Petra Lassuthova33,
  37. Jana Neupauerová33,
  38. Jeff L Waugh34,
  39. Sotirios Keros35,
  40. Jill Clayton-Smith36,
  41. Sarah F Smithson37,
  42. Han G Brunner1,7,
  43. Ceciel van Hoeckel38,
  44. Mel Anderson38,
  45. Virginia E Clowes39,
  46. Victoria Mok Siu40,
  47. The DDD study41,
  48. Paulo Selber42,
  49. Richard J Leventer43,
  50. Christoffer Nellaker44,45,46,
  51. Dierk Niessing2,47,
  52. David Hunt48,49,
  53. Diana Baralle48,49
  1. 1 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
  2. 2 Institute of Structural Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
  3. 3 Visual Geometry Group, Department of Engineering Science, University of Oxford, Oxford, UK
  4. 4 Department of Ophthalmology, Southampton General Hospital, Southampton, UK
  5. 5 Department of Clinical and Experimental Sciences, School of Medicine, University of Southampton, Southampton, UK
  6. 6 Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
  7. 7 Department of Clinical Genetics and School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, The Netherlands
  8. 8 Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands
  9. 9 School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
  10. 10 Academic Center for Epileptology, Kempenhaeghe/MUMC, Maastricht, The Netherlands
  11. 11 Department of Pediatric Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
  12. 12 Department of Pediatrics, Rijnstate Hospital, Arnhem, The Netherlands
  13. 13 Department of Pediatrics, Máxima Medisch Centrum, Veldhoven, The Netherlands
  14. 14 Department of Pediatric Neurology, Academic Medical Center, Amsterdam, The Netherlands
  15. 15 Department of Neurology and Pediatric Neurology, Emma Children’s Hospital/Academic Medical Center, Amsterdam, The Netherlands
  16. 16 SW Thames Regional Genetics Service, St. George’s University NHS Foundation Trust, London, UK
  17. 17 Department of Clinical Genetics, Laboratory Medicine Building, Queen Elizabeth University Hospital, Glasgow, UK
  18. 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. 19 West Midlands Regional Clinical Genetics Service, Birmingham Women’s NHS Foundation Trust, Birmingham, UK
  20. 20 KK Research Laboratory, KK Women’s and Children’s Hospital, Singapore
  21. 21 National University Health Systems, Cardiovascular Research Institute, Singapore, Singapore
  22. 22 Genome Institute of Singapore, Singapore, Singapore
  23. 23 Departmentof Paediatrics, Genetics Service, KK Women’s and Children’s Hospital, Singapore
  24. 24 Department of Clinical Genetics, Royal Devon and Exeter NHS Trust, Exeter, UK
  25. 25 Department of Clinical Genetics, School of Medicine and Medical Science, Our Lady’s Hospital, University College Dublin, Dublin, Ireland
  26. 26 Department of Child Neurology, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  27. 27 Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland
  28. 28 Department of Pediatric Neurology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA
  29. 29 Division of Pediatric Neurology, Seattle Children’s Hospital/University of Washington, Seattle, Washington, USA
  30. 30 Department of Pediatrics, Section of Neurology, St. Christopher’s Hospital for Children, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
  31. 31 Division of Neurology and Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada
  32. 32 The Rina Mor Institute of Medical Genetics, Holon, Israel
  33. 33 Department of Pediatric Neurology, Second Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic
  34. 34 Department of Neurology, Boston Children’s Hospital, Boston, Massachusetts, USA
  35. 35 Sanford Children’s Hospital, University of South Dakota, Sioux Falls, South Dakota, USA
  36. 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. 37 Department of Clinical Genetics, University Hospitals Bristol, Bristol, UK
  38. 38 PURA Syndrome Foundation, Tulsa, Oklahoma, USA
  39. 39 North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, London, UK
  40. 40 Division of Medical Genetics, Department of Pediatrics, Schulich School of Medicine, University of Western Ontario, London, Ontario, Canada
  41. 41 Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
  42. 42 Department of Orthopaedics, Royal Children’s Hospital, Melbourne, Victoria, Australia
  43. 43 Department of Neurology, University of Melbourne Department of Paediatrics, The Royal Children’s Hospital, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
  44. 44 Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK
  45. 45 Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital Women’s Centre, University of Oxford, Oxford, UK
  46. 46 Department of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Oxford, UK
  47. 47 Department of Cell Biology, Biomedical Center of the Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
  48. 48 Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK
  49. 49 Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK
  1. Correspondence to Margot R F Reijnders, Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, Netherlands; margot.reijnders{at} and Dr Diana Baralle, Human Genetic and Genomics, University of Southampton, Human Development and Health, Duthie Building, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK; D.Baralle{at}


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.

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

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  • DH and DB contributed equally.

  • Contributors All authors contributed significantly to this research and in the preparation of the manuscript. MRFR is the first author and along with DH and DB (senior authors) coordinated the group. RJ and DN performed structural modelling of mutations and contributed to the genotype-phenotype analysis. MA and CN performed computational modelling of the PURA face. JES, TvE, MV, RPWR, SJCS, APAS, JS, RP, KvD, ES, CTRMS, LAB, JMC, ME, SM, MW, KEC, SD, NSC, ECT, RF, AHML, JR, AG, TL, PI, SW, IR, KSC, JJD, DLL, KS, PL, JN, JLW, SK, JCS, SFS, HGB, CVH, MA, VEC, VMS, DDD, PS and RJL collected mutational and phenotypic data and contributed to interpretation of the data. All authors have been involved in the drafting, critical revision and final approval of the manuscript for publication. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Funding DH and DB are supported by a grant from the Newlife Foundation, UK. RJL is supported by a Melbourne Children’s Clinician Scientist Fellowship. DN is supported by the Deutsche Forschungsgemeinschaft NI 1110/4-1. KS and PL (JN) are supported by MH CR AZV 15-33041A. The work for patient 29 was partially funded by NMRC/CG/006/2013 from the National Medical Research Council, Ministry of Health, Republic of Singapore. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. None of the funders were involved in study design, data collection, analysis and interpretation, writing of the report or in the decision to submit the paper for publication.

  • Competing interests None declared.

  • Patient consent Guardian consent obtained.

  • Ethics approval Medical Ethics Committee of the Radboud University Medical Center, Nijmegen. The study has UK Research Ethics Committee approval granted by the Cambridge South REC (10/H0305/83) and by the Republic of Ireland REC (GEN/284/12).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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