PURA syndrome: Clinical delineation and genotype-phenotype study in 32 individuals with review of published literature

Margot R.F. Reijnders, Robert Janowski, Mohsan Alvi, Jay E. Self, Ton J. Van Essen, Maaike Vreeburg, Rob P.W. Rouhl, Servi J.C. Stevens, Alexander P.A. Stegmann, Jolanda Schieving, Rolph Pfundt, Katinke Van Dijk, Eric Smeets, Connie T.R.M. Stumpel, Levinus A. Bok, Jan Maarten Cobben, Marc Engelen, Sahar Mansour, Margo Whiteford, Kate E. ChandlerSofia Douzgou, Nicola S. Cooper, Ene Choo Tan, Roger Foo, Angeline H.M. Lai, Julia Rankin, Andrew Green, Tuula Lönnqvist, Pirjo Isohanni, Shelley Williams, Ilene Ruhoy, Karen S. Carvalho, James J. Dowling, Dorit L. Lev, Katalin Sterbova, Petra Lassuthova, Jana Neupauerová, Jeff L. Waugh, Sotirios Keros, Jill Clayton-Smith, Sarah F. Smithson, Han G. Brunner, Ceciel Van Hoeckel, Mel Anderson, Virginia E. Clowes, Victoria Mok Siu, The Ddd Study, Paulo Selber, Richard J. Leventer, Christoffer Nellaker, Dierk Niessing, David Hunt, Diana Baralle

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)104-113
Number of pages10
JournalJournal of Medical Genetics
Volume55
Issue number2
DOIs
StatePublished - Feb 1 2018

Fingerprint

Genotype
Phenotype
Mutation
Genetic Association Studies
Intellectual Disability
Muscle Hypotonia
Epilepsy
Startle Reflex
Disorders of Excessive Somnolence
Exome
Staphylococcal Protein A
Hypothermia
Computer Simulation
Drosophila
Carrier Proteins
Research

Keywords

  • epilepsy and seizures
  • hypotonia
  • intellectual disability
  • neonatal problems
  • PURA syndrome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Reijnders, M. R. F., Janowski, R., Alvi, M., Self, J. E., Van Essen, T. J., Vreeburg, M., ... Baralle, D. (2018). PURA syndrome: Clinical delineation and genotype-phenotype study in 32 individuals with review of published literature. Journal of Medical Genetics, 55(2), 104-113. https://doi.org/10.1136/jmedgenet-2017-104946

PURA syndrome : Clinical delineation and genotype-phenotype study in 32 individuals with review of published literature. / Reijnders, Margot R.F.; Janowski, Robert; Alvi, Mohsan; Self, Jay E.; Van Essen, Ton J.; Vreeburg, Maaike; Rouhl, Rob P.W.; Stevens, Servi J.C.; Stegmann, Alexander P.A.; Schieving, Jolanda; Pfundt, Rolph; Van Dijk, Katinke; Smeets, Eric; Stumpel, Connie T.R.M.; Bok, Levinus A.; Cobben, Jan Maarten; Engelen, Marc; Mansour, Sahar; Whiteford, Margo; Chandler, Kate E.; Douzgou, Sofia; Cooper, Nicola S.; Tan, Ene Choo; Foo, Roger; Lai, Angeline H.M.; Rankin, Julia; Green, Andrew; Lönnqvist, Tuula; Isohanni, Pirjo; Williams, Shelley; Ruhoy, Ilene; Carvalho, Karen S.; Dowling, James J.; Lev, Dorit L.; Sterbova, Katalin; Lassuthova, Petra; Neupauerová, Jana; Waugh, Jeff L.; Keros, Sotirios; Clayton-Smith, Jill; Smithson, Sarah F.; Brunner, Han G.; Van Hoeckel, Ceciel; Anderson, Mel; Clowes, Virginia E.; Siu, Victoria Mok; Ddd Study, The; Selber, Paulo; Leventer, Richard J.; Nellaker, Christoffer; Niessing, Dierk; Hunt, David; Baralle, Diana.

In: Journal of Medical Genetics, Vol. 55, No. 2, 01.02.2018, p. 104-113.

Research output: Contribution to journalArticle

Reijnders, MRF, Janowski, R, Alvi, M, Self, JE, Van Essen, TJ, Vreeburg, M, Rouhl, RPW, Stevens, SJC, Stegmann, APA, Schieving, J, Pfundt, R, Van Dijk, K, Smeets, E, Stumpel, CTRM, Bok, LA, Cobben, JM, Engelen, M, Mansour, S, Whiteford, M, Chandler, KE, Douzgou, S, Cooper, NS, Tan, EC, Foo, R, Lai, AHM, Rankin, J, Green, A, Lönnqvist, T, Isohanni, P, Williams, S, Ruhoy, I, Carvalho, KS, Dowling, JJ, Lev, DL, Sterbova, K, Lassuthova, P, Neupauerová, J, Waugh, JL, Keros, S, Clayton-Smith, J, Smithson, SF, Brunner, HG, Van Hoeckel, C, Anderson, M, Clowes, VE, Siu, VM, Ddd Study, T, Selber, P, Leventer, RJ, Nellaker, C, Niessing, D, Hunt, D & Baralle, D 2018, 'PURA syndrome: Clinical delineation and genotype-phenotype study in 32 individuals with review of published literature', Journal of Medical Genetics, vol. 55, no. 2, pp. 104-113. https://doi.org/10.1136/jmedgenet-2017-104946
Reijnders, Margot R.F. ; Janowski, Robert ; Alvi, Mohsan ; Self, Jay E. ; Van Essen, Ton J. ; Vreeburg, Maaike ; Rouhl, Rob P.W. ; Stevens, Servi J.C. ; Stegmann, Alexander P.A. ; Schieving, Jolanda ; Pfundt, Rolph ; Van Dijk, Katinke ; Smeets, Eric ; Stumpel, Connie T.R.M. ; Bok, Levinus A. ; Cobben, Jan Maarten ; Engelen, Marc ; Mansour, Sahar ; Whiteford, Margo ; Chandler, Kate E. ; Douzgou, Sofia ; Cooper, Nicola S. ; Tan, Ene Choo ; Foo, Roger ; Lai, Angeline H.M. ; Rankin, Julia ; Green, Andrew ; Lönnqvist, Tuula ; Isohanni, Pirjo ; Williams, Shelley ; Ruhoy, Ilene ; Carvalho, Karen S. ; Dowling, James J. ; Lev, Dorit L. ; Sterbova, Katalin ; Lassuthova, Petra ; Neupauerová, Jana ; Waugh, Jeff L. ; Keros, Sotirios ; Clayton-Smith, Jill ; Smithson, Sarah F. ; Brunner, Han G. ; Van Hoeckel, Ceciel ; Anderson, Mel ; Clowes, Virginia E. ; Siu, Victoria Mok ; Ddd Study, The ; Selber, Paulo ; Leventer, Richard J. ; Nellaker, Christoffer ; Niessing, Dierk ; Hunt, David ; Baralle, Diana. / PURA syndrome : Clinical delineation and genotype-phenotype study in 32 individuals with review of published literature. In: Journal of Medical Genetics. 2018 ; Vol. 55, No. 2. pp. 104-113.
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abstract = "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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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 - Van 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 - Lönnqvist, 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 - Neupauerová, 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 - Ddd Study, The

AU - Selber, Paulo

AU - Leventer, Richard J.

AU - Nellaker, Christoffer

AU - Niessing, Dierk

AU - Hunt, David

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 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.

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.

KW - epilepsy and seizures

KW - hypotonia

KW - intellectual disability

KW - neonatal problems

KW - PURA syndrome

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