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PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature
MRF. Reijnders, R. Janowski, M. Alvi, JE. Self, TJ. van Essen, M. Vreeburg, RPW. Rouhl, SJC. Stevens, APA. Stegmann, J. Schieving, R. Pfundt, K. van Dijk, E. Smeets, CTRM. Stumpel, LA. Bok, JM. Cobben, M. Engelen, S. Mansour, M. Whiteford, KE....
Language English Country England, Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't, Review
Grant support
Wellcome Trust - United Kingdom
MR/M014568/1
Medical Research Council - United Kingdom
NV15-33041A
MZ0
CEP Register
Digital library NLK
Full text - Article
Source
NLK
ProQuest Central
from 1994-01-01 to 6 months ago
Health & Medicine (ProQuest)
from 1994-01-01 to 6 months ago
- MeSH
- Eye Abnormalities genetics MeSH
- DNA-Binding Proteins chemistry genetics MeSH
- Genetic Association Studies MeSH
- Humans MeSH
- Intellectual Disability genetics MeSH
- Mutation * MeSH
- Infant, Newborn MeSH
- Face abnormalities MeSH
- Drosophila Proteins chemistry genetics MeSH
- Structural Homology, Protein MeSH
- Muscle Hypotonia etiology genetics MeSH
- Syndrome MeSH
- Pregnancy MeSH
- Transcription Factors chemistry genetics MeSH
- Check Tag
- Humans MeSH
- Infant, Newborn MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
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.
Department of Clinical Genetics Royal Devon and Exeter NHS Trust Exeter UK
Department of Clinical Genetics University Hospitals Bristol Bristol UK
Department of Human Genetics Radboud University Medical Center Nijmegen The Netherlands
Department of Neurology Boston Children's Hospital Boston Massachusetts USA
Department of Orthopaedics Royal Children's Hospital Melbourne Victoria Australia
Department of Pediatric Neurology Academic Medical Center Amsterdam The Netherlands
Department of Pediatrics Máxima Medisch Centrum Veldhoven The Netherlands
Department of Pediatrics Rijnstate Hospital Arnhem The Netherlands
Departmentof Paediatrics Genetics Service KK Women's and Children's Hospital Singapore
KK Research Laboratory KK Women's and Children's Hospital Singapore
North West Thames Regional Genetics Service London North West Healthcare NHS Trust London UK
PURA Syndrome Foundation Tulsa Oklahoma USA
Sanford Children's Hospital University of South Dakota Sioux Falls South Dakota USA
SW Thames Regional Genetics Service St George's University NHS Foundation Trust London UK
The Rina Mor Institute of Medical Genetics Holon Israel
Visual Geometry Group Department of Engineering Science University of Oxford Oxford UK
References provided by Crossref.org
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- $a Reijnders, Margot R F $u Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
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- $a PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature / $c MRF. Reijnders, R. Janowski, M. Alvi, JE. Self, TJ. van Essen, M. Vreeburg, RPW. Rouhl, SJC. Stevens, APA. Stegmann, J. Schieving, R. Pfundt, K. van Dijk, E. Smeets, CTRM. Stumpel, LA. Bok, JM. Cobben, M. Engelen, S. Mansour, M. Whiteford, KE. Chandler, S. Douzgou, NS. Cooper, EC. Tan, R. Foo, AHM. Lai, J. Rankin, A. Green, T. Lönnqvist, P. Isohanni, S. Williams, I. Ruhoy, KS. Carvalho, JJ. Dowling, DL. Lev, K. Sterbova, P. Lassuthova, J. Neupauerová, JL. Waugh, S. Keros, J. Clayton-Smith, SF. Smithson, HG. Brunner, C. van Hoeckel, M. Anderson, VE. Clowes, VM. Siu, T. Ddd Study, P. Selber, RJ. Leventer, C. Nellaker, D. Niessing, D. Hunt, D. Baralle,
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- $a 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.
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