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. Chandler; Sofia 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

doi:10.1136/jmedgenet-2017-104946

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 journal › Article › peer-review

55 Scopus citations

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 language	English (US)
Pages (from-to)	104-113
Number of pages	10
Journal	Journal of medical genetics
Volume	55
Issue number	2
DOIs	https://doi.org/10.1136/jmedgenet-2017-104946
State	Published - Feb 1 2018

Keywords

PURA syndrome
epilepsy and seizures
hypotonia
intellectual disability
neonatal problems

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1136/jmedgenet-2017-104946

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Reijnders, M. R. F., Janowski, R., Alvi, M., Self, J. E., Van Essen, T. J., Vreeburg, M., Rouhl, R. P. W., Stevens, S. J. C., Stegmann, A. P. A., Schieving, J., Pfundt, R., Van Dijk, K., Smeets, E., Stumpel, C. T. R. M., Bok, L. A., Cobben, J. M., Engelen, M., Mansour, S., Whiteford, 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

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

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

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.",

keywords = "PURA syndrome, epilepsy and seizures, hypotonia, intellectual disability, neonatal problems",

author = "Reijnders, {Margot R.F.} and Robert Janowski and Mohsan Alvi and Self, {Jay E.} and {Van Essen}, {Ton J.} and Maaike Vreeburg and Rouhl, {Rob P.W.} and Stevens, {Servi J.C.} and Stegmann, {Alexander P.A.} and Jolanda Schieving and Rolph Pfundt and {Van Dijk}, Katinke and Eric Smeets and Stumpel, {Connie T.R.M.} and Bok, {Levinus A.} and Cobben, {Jan Maarten} and Marc Engelen and Sahar Mansour and Margo Whiteford and Chandler, {Kate E.} and Sofia Douzgou and Cooper, {Nicola S.} and Tan, {Ene Choo} and Roger Foo and Lai, {Angeline H.M.} and Julia Rankin and Andrew Green and Tuula L{\"o}nnqvist and Pirjo Isohanni and Shelley Williams and Ilene Ruhoy and Carvalho, {Karen S.} and Dowling, {James J.} and Lev, {Dorit L.} and Katalin Sterbova and Petra Lassuthova and Jana Neupauerov{\'a} and Waugh, {Jeff L.} and Sotirios Keros and Jill Clayton-Smith and Smithson, {Sarah F.} and Brunner, {Han G.} and {Van Hoeckel}, Ceciel and Mel Anderson and Clowes, {Virginia E.} and Siu, {Victoria Mok} and {Ddd Study}, The and Paulo Selber and Leventer, {Richard J.} and Christoffer Nellaker and Dierk Niessing and David Hunt and Diana Baralle",

year = "2018",

month = feb,

day = "1",

doi = "10.1136/jmedgenet-2017-104946",

language = "English (US)",

volume = "55",

pages = "104--113",

journal = "Journal of medical genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "2",

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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 - PURA syndrome

KW - epilepsy and seizures

KW - hypotonia

KW - intellectual disability

KW - neonatal problems

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SN - 0022-2593

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JO - Journal of medical genetics

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ER -

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

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