Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

Ivan Ivanovski, Olivera Djuric, Stefano Giuseppe Caraffi, Daniela Santodirocco, Marzia Pollazzon, Simonetta Rosato, Duccio Maria Cordelli, Ebtesam Abdalla, Patrizia Accorsi, Margaret P Adam, Paola Francesca Ajmone, Magdalena Badura-Stronka, Chiara Baldo, Maddalena Baldi, Allan Bayat, Stefania Bigoni, Federico Bonvicini, Jeroen Breckpot, Bert Callewaert, Guido CocchiGoran Cuturilo, Daniele De Brasi, Koenraad Devriendt, Mary Beth Dinulos, Tina Duelund Hjortshøj, Roberta Epifanio, Francesca Faravelli, Agata Fiumara, Debora Formisano, Lucio Giordano, Marina Grasso, Sabine Grønborg, Alessandro Iodice, Lorenzo Iughetti, Vladimir Kuburovic, Anna Kutkowska-Kazmierczak, Didier Lacombe, Caterina Lo Rizzo, Anna Luchetti, Baris Malbora, Isabella Mammi, Francesca Mari, Giulia Montorsi, Sebastien Moutton, Rikke S Møller, Petra Muschke, Jens Erik Klint Nielsen, Ewa Obersztyn, Chiara Pantaleoni, Alessandro Pellicciari, Maria Antonietta Pisanti, Igor Prpic, Maria Luisa Poch-Olive, Federico Raviglione, Alessandra Renieri, Emilia Ricci, Francesca Rivieri, Gijs W Santen, Salvatore Savasta, Gioacchino Scarano, Ina Schanze, Angelo Selicorni, Margherita Silengo, Robert Smigiel, Luigina Spaccini, Giovanni Sorge, Krzysztof Szczaluba, Luigi Tarani, Luis Gonzaga Tone, Annick Toutain, Aurelien Trimouille, Elvis Terci Valera, Samantha Schrier Vergano, Nicoletta Zanotta, Martin Zenker, Andrea Conidi, Marcella Zollino, Anita Rauch, Christiane Zweier, Livia Garavelli

Research output: Contribution to journalArticle

Abstract

PURPOSE: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.

METHODS: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.

RESULTS: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.

CONCLUSION: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.

Original languageEnglish
Pages (from-to)965-975
Number of pages11
JournalGenetics in Medicine
Volume20
Issue number9
DOIs
Publication statusPublished - Sep 2018

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Genotype
Phenotype
Mutation
Genetic Association Studies
Natural History
Intellectual Disability
Patient Care
Mowat-Wilson syndrome
Genes
Proteins

Cite this

Ivanovski, I., Djuric, O., Caraffi, S. G., Santodirocco, D., Pollazzon, M., Rosato, S., ... Garavelli, L. (2018). Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care. Genetics in Medicine, 20(9), 965-975. https://doi.org/10.1038/gim.2017.221

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care. / Ivanovski, Ivan; Djuric, Olivera; Caraffi, Stefano Giuseppe; Santodirocco, Daniela; Pollazzon, Marzia; Rosato, Simonetta; Cordelli, Duccio Maria; Abdalla, Ebtesam; Accorsi, Patrizia; Adam, Margaret P; Ajmone, Paola Francesca; Badura-Stronka, Magdalena; Baldo, Chiara; Baldi, Maddalena; Bayat, Allan; Bigoni, Stefania; Bonvicini, Federico; Breckpot, Jeroen; Callewaert, Bert; Cocchi, Guido; Cuturilo, Goran; De Brasi, Daniele; Devriendt, Koenraad; Dinulos, Mary Beth; Hjortshøj, Tina Duelund; Epifanio, Roberta; Faravelli, Francesca; Fiumara, Agata; Formisano, Debora; Giordano, Lucio; Grasso, Marina; Grønborg, Sabine; Iodice, Alessandro; Iughetti, Lorenzo; Kuburovic, Vladimir; Kutkowska-Kazmierczak, Anna; Lacombe, Didier; Lo Rizzo, Caterina; Luchetti, Anna; Malbora, Baris; Mammi, Isabella; Mari, Francesca; Montorsi, Giulia; Moutton, Sebastien; Møller, Rikke S; Muschke, Petra; Nielsen, Jens Erik Klint; Obersztyn, Ewa; Pantaleoni, Chiara; Pellicciari, Alessandro; Pisanti, Maria Antonietta; Prpic, Igor; Poch-Olive, Maria Luisa; Raviglione, Federico; Renieri, Alessandra; Ricci, Emilia; Rivieri, Francesca; Santen, Gijs W; Savasta, Salvatore; Scarano, Gioacchino; Schanze, Ina; Selicorni, Angelo; Silengo, Margherita; Smigiel, Robert; Spaccini, Luigina; Sorge, Giovanni; Szczaluba, Krzysztof; Tarani, Luigi; Tone, Luis Gonzaga; Toutain, Annick; Trimouille, Aurelien; Valera, Elvis Terci; Vergano, Samantha Schrier; Zanotta, Nicoletta; Zenker, Martin; Conidi, Andrea; Zollino, Marcella; Rauch, Anita; Zweier, Christiane; Garavelli, Livia.

In: Genetics in Medicine, Vol. 20, No. 9, 09.2018, p. 965-975.

Research output: Contribution to journalArticle

Ivanovski, I, Djuric, O, Caraffi, SG, Santodirocco, D, Pollazzon, M, Rosato, S, Cordelli, DM, Abdalla, E, Accorsi, P, Adam, MP, Ajmone, PF, Badura-Stronka, M, Baldo, C, Baldi, M, Bayat, A, Bigoni, S, Bonvicini, F, Breckpot, J, Callewaert, B, Cocchi, G, Cuturilo, G, De Brasi, D, Devriendt, K, Dinulos, MB, Hjortshøj, TD, Epifanio, R, Faravelli, F, Fiumara, A, Formisano, D, Giordano, L, Grasso, M, Grønborg, S, Iodice, A, Iughetti, L, Kuburovic, V, Kutkowska-Kazmierczak, A, Lacombe, D, Lo Rizzo, C, Luchetti, A, Malbora, B, Mammi, I, Mari, F, Montorsi, G, Moutton, S, Møller, RS, Muschke, P, Nielsen, JEK, Obersztyn, E, Pantaleoni, C, Pellicciari, A, Pisanti, MA, Prpic, I, Poch-Olive, ML, Raviglione, F, Renieri, A, Ricci, E, Rivieri, F, Santen, GW, Savasta, S, Scarano, G, Schanze, I, Selicorni, A, Silengo, M, Smigiel, R, Spaccini, L, Sorge, G, Szczaluba, K, Tarani, L, Tone, LG, Toutain, A, Trimouille, A, Valera, ET, Vergano, SS, Zanotta, N, Zenker, M, Conidi, A, Zollino, M, Rauch, A, Zweier, C & Garavelli, L 2018, 'Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care', Genetics in Medicine, vol. 20, no. 9, pp. 965-975. https://doi.org/10.1038/gim.2017.221
Ivanovski I, Djuric O, Caraffi SG, Santodirocco D, Pollazzon M, Rosato S et al. Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care. Genetics in Medicine. 2018 Sep;20(9):965-975. https://doi.org/10.1038/gim.2017.221
Ivanovski, Ivan ; Djuric, Olivera ; Caraffi, Stefano Giuseppe ; Santodirocco, Daniela ; Pollazzon, Marzia ; Rosato, Simonetta ; Cordelli, Duccio Maria ; Abdalla, Ebtesam ; Accorsi, Patrizia ; Adam, Margaret P ; Ajmone, Paola Francesca ; Badura-Stronka, Magdalena ; Baldo, Chiara ; Baldi, Maddalena ; Bayat, Allan ; Bigoni, Stefania ; Bonvicini, Federico ; Breckpot, Jeroen ; Callewaert, Bert ; Cocchi, Guido ; Cuturilo, Goran ; De Brasi, Daniele ; Devriendt, Koenraad ; Dinulos, Mary Beth ; Hjortshøj, Tina Duelund ; Epifanio, Roberta ; Faravelli, Francesca ; Fiumara, Agata ; Formisano, Debora ; Giordano, Lucio ; Grasso, Marina ; Grønborg, Sabine ; Iodice, Alessandro ; Iughetti, Lorenzo ; Kuburovic, Vladimir ; Kutkowska-Kazmierczak, Anna ; Lacombe, Didier ; Lo Rizzo, Caterina ; Luchetti, Anna ; Malbora, Baris ; Mammi, Isabella ; Mari, Francesca ; Montorsi, Giulia ; Moutton, Sebastien ; Møller, Rikke S ; Muschke, Petra ; Nielsen, Jens Erik Klint ; Obersztyn, Ewa ; Pantaleoni, Chiara ; Pellicciari, Alessandro ; Pisanti, Maria Antonietta ; Prpic, Igor ; Poch-Olive, Maria Luisa ; Raviglione, Federico ; Renieri, Alessandra ; Ricci, Emilia ; Rivieri, Francesca ; Santen, Gijs W ; Savasta, Salvatore ; Scarano, Gioacchino ; Schanze, Ina ; Selicorni, Angelo ; Silengo, Margherita ; Smigiel, Robert ; Spaccini, Luigina ; Sorge, Giovanni ; Szczaluba, Krzysztof ; Tarani, Luigi ; Tone, Luis Gonzaga ; Toutain, Annick ; Trimouille, Aurelien ; Valera, Elvis Terci ; Vergano, Samantha Schrier ; Zanotta, Nicoletta ; Zenker, Martin ; Conidi, Andrea ; Zollino, Marcella ; Rauch, Anita ; Zweier, Christiane ; Garavelli, Livia. / Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care. In: Genetics in Medicine. 2018 ; Vol. 20, No. 9. pp. 965-975.
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abstract = "PURPOSE: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.METHODS: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.RESULTS: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.CONCLUSION: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.",
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T1 - Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

AU - Ivanovski, Ivan

AU - Djuric, Olivera

AU - Caraffi, Stefano Giuseppe

AU - Santodirocco, Daniela

AU - Pollazzon, Marzia

AU - Rosato, Simonetta

AU - Cordelli, Duccio Maria

AU - Abdalla, Ebtesam

AU - Accorsi, Patrizia

AU - Adam, Margaret P

AU - Ajmone, Paola Francesca

AU - Badura-Stronka, Magdalena

AU - Baldo, Chiara

AU - Baldi, Maddalena

AU - Bayat, Allan

AU - Bigoni, Stefania

AU - Bonvicini, Federico

AU - Breckpot, Jeroen

AU - Callewaert, Bert

AU - Cocchi, Guido

AU - Cuturilo, Goran

AU - De Brasi, Daniele

AU - Devriendt, Koenraad

AU - Dinulos, Mary Beth

AU - Hjortshøj, Tina Duelund

AU - Epifanio, Roberta

AU - Faravelli, Francesca

AU - Fiumara, Agata

AU - Formisano, Debora

AU - Giordano, Lucio

AU - Grasso, Marina

AU - Grønborg, Sabine

AU - Iodice, Alessandro

AU - Iughetti, Lorenzo

AU - Kuburovic, Vladimir

AU - Kutkowska-Kazmierczak, Anna

AU - Lacombe, Didier

AU - Lo Rizzo, Caterina

AU - Luchetti, Anna

AU - Malbora, Baris

AU - Mammi, Isabella

AU - Mari, Francesca

AU - Montorsi, Giulia

AU - Moutton, Sebastien

AU - Møller, Rikke S

AU - Muschke, Petra

AU - Nielsen, Jens Erik Klint

AU - Obersztyn, Ewa

AU - Pantaleoni, Chiara

AU - Pellicciari, Alessandro

AU - Pisanti, Maria Antonietta

AU - Prpic, Igor

AU - Poch-Olive, Maria Luisa

AU - Raviglione, Federico

AU - Renieri, Alessandra

AU - Ricci, Emilia

AU - Rivieri, Francesca

AU - Santen, Gijs W

AU - Savasta, Salvatore

AU - Scarano, Gioacchino

AU - Schanze, Ina

AU - Selicorni, Angelo

AU - Silengo, Margherita

AU - Smigiel, Robert

AU - Spaccini, Luigina

AU - Sorge, Giovanni

AU - Szczaluba, Krzysztof

AU - Tarani, Luigi

AU - Tone, Luis Gonzaga

AU - Toutain, Annick

AU - Trimouille, Aurelien

AU - Valera, Elvis Terci

AU - Vergano, Samantha Schrier

AU - Zanotta, Nicoletta

AU - Zenker, Martin

AU - Conidi, Andrea

AU - Zollino, Marcella

AU - Rauch, Anita

AU - Zweier, Christiane

AU - Garavelli, Livia

PY - 2018/9

Y1 - 2018/9

N2 - PURPOSE: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.METHODS: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.RESULTS: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.CONCLUSION: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.

AB - PURPOSE: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.METHODS: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.RESULTS: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.CONCLUSION: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.

U2 - 10.1038/gim.2017.221

DO - 10.1038/gim.2017.221

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JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

IS - 9

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