TY - JOUR
T1 - PURA syndrome
T2 - clinical delineation and genotype-phenotype study in 32 individuals with review of published literature
AU - Reijnders, Margot R. F.
AU - Janowski, Robert
AU - Alvi, Mohsan
AU - Self, Jay E.
AU - van Essen, Ton J.
AU - Vreeburg, Maaike
AU - Rouhl, Rob P. W.
AU - Stevens, Servi J. C.
AU - Stegmann, Alexander P. A.
AU - Schieving, Jolanda
AU - Pfundt, Rolph
AU - Dijk, Katinke
AU - Smeets, Eric
AU - Stumpel, Connie T. R. M.
AU - Bok, Levinus A.
AU - Cobben, Jan Maarten
AU - Engelen, Marc
AU - Mansour, Sahar
AU - Whiteford, Margo
AU - Chandler, Kate E.
AU - Douzgou, Sofia
AU - Cooper, Nicola S.
AU - Tan, Ene-Choo
AU - Foo, Roger
AU - Lai, Angeline H. M.
AU - Rankin, Julia
AU - Green, Andrew
AU - Lonnqvist, Tuula
AU - Isohanni, Pirjo
AU - Williams, Shelley
AU - Ruhoy, Ilene
AU - Carvalho, Karen S.
AU - Dowling, James J.
AU - Lev, Dorit L.
AU - Sterbova, Katalin
AU - Lassuthova, Petra
AU - Neupauerova, Jana
AU - Waugh, Jeff L.
AU - Keros, Sotirios
AU - Clayton-Smith, Jill
AU - Smithson, Sarah F.
AU - Brunner, Han G.
AU - van Hoeckel, Ceciel
AU - Anderson, Mel
AU - Clowes, Virginia E.
AU - Siu, Victoria Mok
AU - Selber, Paulo
AU - Leventer, Richard J.
AU - Nellaker, Christoffer
AU - Niessing, Dierk
AU - DDD Study
AU - Baralle, Diana
PY - 2018/2/1
Y1 - 2018/2/1
N2 - 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.
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 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.
KW - 5Q31.3 MICRODELETION SYNDROME
KW - POSTNATAL BRAIN-DEVELOPMENT
KW - ALPHA
KW - REVEALS
KW - PATIENT
KW - GENES
U2 - 10.1136/jmedgenet-2017-104946
DO - 10.1136/jmedgenet-2017-104946
M3 - (Systematic) Review article
C2 - 29097605
SN - 0022-2593
VL - 55
SP - 104
EP - 113
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 2
ER -