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

Margot R.F. Reijnders, Robert Janowski, Mohsan Alvi, Jay E. Self, Ton J. Van Essen, Maaike Vreeburg, Rob P.W. Rouhl, Servi J.C. Stevens, Alexander P.A. Stegmann, Jolanda Schieving, Rolph Pfundt, Katinke Van Dijk, Eric Smeets, Connie T.R.M. Stumpel, Levinus A. Bok, Jan Maarten Cobben, Marc Engelen, Sahar Mansour, Margo Whiteford, Kate E. ChandlerSofia Douzgou, Nicola S. Cooper, Ene Choo Tan, Roger Foo, Angeline H.M. Lai, Julia Rankin, Andrew Green, Tuula Lönnqvist, Pirjo Isohanni, Shelley Williams, Ilene Ruhoy, Karen S. Carvalho, James J. Dowling, Dorit L. Lev, Katalin Sterbova, Petra Lassuthova, Jana Neupauerová, Jeff L. Waugh, Sotirios Keros, Jill Clayton-Smith, Sarah F. Smithson, Han G. Brunner, Ceciel Van Hoeckel, Mel Anderson, Virginia E. Clowes, Victoria Mok Siu, The Ddd Study, Paulo Selber, Richard J. Leventer, Christoffer Nellaker, Dierk Niessing, David Hunt, Diana Baralle

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)104-113
Number of pages10
JournalJournal of medical genetics
Issue number2
StatePublished - Feb 1 2018


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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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