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 Cocchi; Goran 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

doi:10.1038/gim.2017.221

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

Department of Clinical Medicine

30 Citations (Scopus)

24 Downloads (Pure)

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 language	English
Journal	Genetics In Medicine
Volume	20
Issue number	9
Pages (from-to)	965-975
ISSN	1098-3600
DOIs	https://doi.org/10.1038/gim.2017.221
Publication status	Published - 1 Sept 2018

Keywords

Abnormalities, Multiple/genetics
Adolescent
Adult
Child
Child, Preschool
Facies
Female
Genetic Association Studies/methods
Genotype
Hirschsprung Disease/diagnosis
Humans
Infant
Intellectual Disability/diagnosis
Male
Microcephaly/diagnosis
Mutation
Phenotype
Zinc Finger E-box Binding Homeobox 2/genetics

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Ivanovski, I., Djuric, O., Caraffi, S. G., Santodirocco, D., Pollazzon, M., Rosato, S., Cordelli, D. M., Abdalla, E., Accorsi, P., Adam, M. P., Ajmone, P. F., Badura-Stronka, M., Baldo, C., Baldi, M., Bayat, A., Bigoni, S., Bonvicini, F., Breckpot, J., Callewaert, B., ... 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

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

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

year = "2018",

month = sep,

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doi = "10.1038/gim.2017.221",

language = "English",

volume = "20",

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journal = "Genetics in Medicine",

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TY - JOUR

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 - 2018/9/1

Y1 - 2018/9/1

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.

KW - Abnormalities, Multiple/genetics

KW - Adolescent

KW - Adult

KW - Child

KW - Child, Preschool

KW - Facies

KW - Female

KW - Genetic Association Studies/methods

KW - Genotype

KW - Hirschsprung Disease/diagnosis

KW - Humans

KW - Infant

KW - Intellectual Disability/diagnosis

KW - Male

KW - Microcephaly/diagnosis

KW - Mutation

KW - Phenotype

KW - Zinc Finger E-box Binding Homeobox 2/genetics

U2 - 10.1038/gim.2017.221

DO - 10.1038/gim.2017.221

M3 - Journal article

C2 - 29300384

SN - 1098-3600

VL - 20

SP - 965

EP - 975

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 9

ER -

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

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Keywords

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