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 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 Lonnqvist, Pirjo Isohanni, Shelley Williams, Ilene Ruhoy, Karen S. Carvalho, James J. Dowling, Dorit L. Lev, Katalin Sterbova, Petra Lassuthova, Jana Neupauerova, 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, Paulo Selber, Richard J. Leventer, Christoffer Nellaker, Dierk Niessing, DDD Study, Diana Baralle*

*Corresponding author for this work

Research output: Contribution to journal(Systematic) Review article peer-review


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 T o 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 genotypephenotype 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
Pages (from-to)104-113
Number of pages10
JournalJournal of Medical Genetics
Issue number2
Publication statusPublished - 1 Feb 2018



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