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
- 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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