A missense mutation in the <i>ZFHX1B</i> gene associated with an atypical Mowat–Wilson syndrome phenotype

Heinritz, Wolfram; Zweier, Christiane; Froster, Ursula G.; Strenge, Sibylle; Kujat, Annegret; Syrbe, Steffen; Rauch, Anita; Schuster, Volker

doi:10.1002/ajmg.a.31267

Cited by 35 publications

(33 citation statements)

References 17 publications

(25 reference statements)

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“…More than 110 different molecular anomalies are described today [Amiel et al, 2001;Yamada et al, 2001;Yoneda et al, 2002;Zweier et al, 2002Zweier et al, , 2005Zweier et al, , 2006Garavelli et al, 2003;Wilson et al, 2003;Cerruti Mainardi et al, 2004;Gregory-Evans et al, 2004;Ishihara et al, 2004;Heinritz et al, 2006]. All are found in the heterozygous state.…”

Section: Mowat-wilson Syndrome (Mws; Mim] 235730mentioning

confidence: 95%

ZFHX1B mutations in patients with Mowat-Wilson syndrome

et al. 2007

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Mowat-Wilson syndrome (MWS) is a recently delineated mental retardation (MR)-multiple congenital anomaly syndrome, characterized by typical facies, severe MR, epilepsy, and variable congenital malformations, including Hirschsprung disease (HSCR), genital anomalies, congenital heart disease (CHD), and agenesis of the corpus callosum (ACC). It is caused by de novo heterozygous mutations or deletions of the ZFHX1B gene located at 2q22. ZFHX1B encodes Smad-interacting protein-1 (SMADIP1 or SIP1), a transcriptional corepressor involved in the transforming growth factor-beta signaling pathway. It is a highly evolutionarily conserved gene, widely expressed in embryological development. Over 100 mutations have been described in patients with clinically typical MWS, who almost always have whole gene deletions or truncating mutations (nonsense or frameshift) of ZFHX1B, suggesting that haploinsufficiency is the basis of MWS pathology. No obvious genotype-phenotype correlation could be identified so far, but atypical phenotypes have been reported with missense or splice mutations in the ZFHX1B gene. In this work we describe 40 novel mutations and we summarize the various mutational reports published since the identification of the causative gene.

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Section: Mowat-wilson Syndrome (Mws; Mim] 235730mentioning

confidence: 95%

ZFHX1B mutations in patients with Mowat-Wilson syndrome

et al. 2007

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“…This represents the fourth instance of sibling recurrence [McGaughran et al, 2005;Zweier et al, 2005;Mowat, personal communication;Ohtsuka et al, 2008], due to most likely germ-line mosaicism. Lurie et al [1994], Mowat et al [1998Mowat et al [ , 2003, Amiel et al [2001], Cacheux et al [2001], Kaariainen et al [2001], Rauch et al [2001], Wakamatsu et al [2001], Yamada et al [2001], Nagaya et al [2002], Yoneda et al [2002], Zweier et al [2002Zweier et al [ , 2003Zweier et al [ , 2005Zweier et al [ , 2006, Garavelli et al [2003], Sztriha et al [2003], Wilson et al [2003], Cerruti-Mainardi et al [2004], Gregory-Evans et al [2004], Horn et al [2004], Ishihara et al [2004], Silengo et al [2004], Garavelli et al [2005], McGaughran et al [2005], , Adam et al [2006Adam et al [ , 2008a, Heinritz et al [2006], , Dastot-Le et al [2007], Garavelli and Cerruti Mainardi [2007], Hoffer et al [2007], Sasongko et al [2007], Strenge et al [2007], , Ohtsuka et al [2008], Sasso et al [2008]. b Without the six cases already published [Garavelli et al, 2003;Cerruti-Mainardi et al, 2004;…”

Section: Genotypementioning

confidence: 99%

“…In 2002, Zweier et al defined a distinct phenotype of Mowat-Wilson syndrome (MWS) caused by mutations in the ZEB2 gene, with or without HSCR. A total of 179 cases have since been reported [Lurie et al, 1994;Mowat et al, 1998;Amiel et al, 2001;Cacheux et al, 2001;K€ a€ ari€ ainen et al, 2001;Rauch et al, 2001;Wakamatsu et al, 2001;Yamada et al, 2001;Nagaya et al, 2002;Yoneda et al, 2002;Zweier et al, 2002Zweier et al, , 2003Zweier et al, , 2005Zweier et al, , 2006Garavelli et al, 2003;Mowat et al, 2003;Silengo et al, 2003Silengo et al, , 2004Sztriha et al, 2003;Wilson et al, 2003;Cerruti-Mainardi et al, 2004Gregory-Evans et al, 2004;Horn et al, 2004;Ishihara et al, 2004;Garavelli et al, 2005;McGaughran et al, 2005;Adam et al, 2006Adam et al, , 2008aHeinritz et al, 2006;Dastot-Le et al, 2007;Garavelli and Cerruti Mainardi, 2007;Hoffer et al, 2007;Sasongko et al, 2007;Strenge et al, 2007;Electronic Database Information: Online Mendelian Inheritance in Man (OMIM) (TM), 2008; Ohtsuka et al, 2008;Sasso et al, 2008].…”

Section: Introductionmentioning

confidence: 99%

Mowat–Wilson syndrome: Facial phenotype changing with age: Study of 19 Italian patients and review of the literature

Garavelli

Zollino²,

Mainardi

et al. 2009

American J of Med Genetics Pt A

103

101

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Mowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene, and characterized by typical face, moderate-to-severe mental retardation, epilepsy, Hirschsprung disease, and multiple congenital anomalies, including genital anomalies (particularly hypospadias in males), congenital heart defects, agenesis of the corpus callosum, and eye defects. Since the first delineation by Mowat et al. [Mowat et al. (1998); J Med Genet 35:617-623], approximately 179 patients with ZEB2 mutations, deletions or cytogenetic abnormalities have been reported primarily from Europe, Australia and the United States. Genetic defects include chromosome 2q21-q23 microdeletions (or different chromosome rearrangements) in few patients, and ZEB2 mutations in most. We report on clinical and genetic data from 19 Italian patients, diagnosed within the last 5 years, including six previously published, and compare them with patients already reported. The main purpose of this review is to underline a highly consistent phenotype and to highlight the phenotypic evolution occurring with age, particularly of the facial characteristics. The prevalence of MWS is likely to be underestimated. Knowledge of the phenotypic spectrum of MWS and of its changing phenotype with age can improve the detection rate of this condition.

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“…Missense mutations of ZEB2 are a rare occurrence and were found in none of our cases. They have been described in the literature in association with mild presentations sharing some similarity with MWS, 31,32 although it is debatable whether most of these atypical cases should actually be classified as MWS. However, in addition to patients with missense mutations, there are a few cases also expected to behave differently than typical haploinsufficiency.…”

Section: Serious Infections Sepsismentioning

confidence: 99%

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

Ivanovski

Djurić

Caraffi

et al. 2018

Genetics in Medicine

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131

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ORIGINAL RESEARCH ARTICLEPurpose: 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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A missense mutation in the ZFHX1B gene associated with an atypical Mowat–Wilson syndrome phenotype

Cited by 35 publications

References 17 publications

ZFHX1B mutations in patients with Mowat-Wilson syndrome

ZFHX1B mutations in patients with Mowat-Wilson syndrome

Mowat–Wilson syndrome: Facial phenotype changing with age: Study of 19 Italian patients and review of the literature

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

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