PT - JOURNAL ARTICLE AU - Margot R F Reijnders AU - Robert Janowski AU - Mohsan Alvi AU - Jay E Self AU - Ton J van Essen AU - Maaike Vreeburg AU - Rob P W Rouhl AU - Servi J C Stevens AU - Alexander P A Stegmann AU - Jolanda Schieving AU - Rolph Pfundt AU - Katinke van Dijk AU - Eric Smeets AU - Connie T R M Stumpel AU - Levinus A Bok AU - Jan Maarten Cobben AU - Marc Engelen AU - Sahar Mansour AU - Margo Whiteford AU - Kate E Chandler AU - Sofia Douzgou AU - Nicola S Cooper AU - Ene-Choo Tan AU - Roger Foo AU - Angeline H M Lai AU - Julia Rankin AU - Andrew Green AU - Tuula Lönnqvist AU - Pirjo Isohanni AU - Shelley Williams AU - Ilene Ruhoy AU - Karen S Carvalho AU - James J Dowling AU - Dorit L Lev AU - Katalin Sterbova AU - Petra Lassuthova AU - Jana Neupauerová AU - Jeff L Waugh AU - Sotirios Keros AU - Jill Clayton-Smith AU - Sarah F Smithson AU - Han G Brunner AU - Ceciel van Hoeckel AU - Mel Anderson AU - Virginia E Clowes AU - Victoria Mok Siu AU - The DDD study AU - Paulo Selber AU - Richard J Leventer AU - Christoffer Nellaker AU - Dierk Niessing AU - David Hunt AU - Diana Baralle TI - PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature AID - 10.1136/jmedgenet-2017-104946 DP - 2017 Nov 02 TA - Journal of Medical Genetics PG - jmedgenet-2017-104946 4099 - http://jmg.bmj.com/content/early/2017/11/02/jmedgenet-2017-104946.short 4100 - http://jmg.bmj.com/content/early/2017/11/02/jmedgenet-2017-104946.full 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.