RT Journal Article SR Electronic T1 PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2017-104946 DO 10.1136/jmedgenet-2017-104946 A1 Margot R F Reijnders A1 Robert Janowski A1 Mohsan Alvi A1 Jay E Self A1 Ton J van Essen A1 Maaike Vreeburg A1 Rob P W Rouhl A1 Servi J C Stevens A1 Alexander P A Stegmann A1 Jolanda Schieving A1 Rolph Pfundt A1 Katinke van Dijk A1 Eric Smeets A1 Connie T R M Stumpel A1 Levinus A Bok A1 Jan Maarten Cobben A1 Marc Engelen A1 Sahar Mansour A1 Margo Whiteford A1 Kate E Chandler A1 Sofia Douzgou A1 Nicola S Cooper A1 Ene-Choo Tan A1 Roger Foo A1 Angeline H M Lai A1 Julia Rankin A1 Andrew Green A1 Tuula Lönnqvist A1 Pirjo Isohanni A1 Shelley Williams A1 Ilene Ruhoy A1 Karen S Carvalho A1 James J Dowling A1 Dorit L Lev A1 Katalin Sterbova A1 Petra Lassuthova A1 Jana Neupauerová A1 Jeff L Waugh A1 Sotirios Keros A1 Jill Clayton-Smith A1 Sarah F Smithson A1 Han G Brunner A1 Ceciel van Hoeckel A1 Mel Anderson A1 Virginia E Clowes A1 Victoria Mok Siu A1 The DDD study A1 Paulo Selber A1 Richard J Leventer A1 Christoffer Nellaker A1 Dierk Niessing A1 David Hunt A1 Diana Baralle YR 2017 UL http://jmg.bmj.com/content/early/2017/11/02/jmedgenet-2017-104946.abstract AB 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.