Recurrence of Mowat-Wilson syndrome in siblings with the same proven mutation

Queensland Clinical Genetics Service, Royal Children's Hospital, Brisbane, Queensland, Australia.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 09/2005; 137A(3):302-4. DOI: 10.1002/ajmg.a.30896
Source: PubMed


Mowat-Wilson syndrome (MWS) is a mental retardation syndrome associated with distinctive facial features, microcephaly, epilepsy, and a variable spectrum of congenital anomalies, including Hirschsprung disease (HSCR), agenesis of the corpus callosum, genitourinary abnormalities, and congenital heart disease. Heterozygous mutations or deletions involving the gene ZFHX1B (previously SIP1) [OMIM 605802] have recently been found to cause MWS. There have previously been no reports of a sibling recurrence of this syndrome. A brother and sister are described with clinical features of MWS, where both have the same truncating mutation in exon 8 of ZFHX1B. As their parents are phenotypically normal and do not have the mutation in lymphocyte-derived DNA, the most likely explanation is germ-line mosaicism.

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Available from: Julie Mcgaughran, Sep 22, 2014
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    • "The parents of MWS patients are usually healthy, and genetic abnormalities including apparent somatic mosaicism have not been reported. However, four families with MWS in siblings have been reported to be likely caused by germ-line mosaicism [McGaughran et al., 2005; Zweier et al., 2005; Cecconi et al., 2008; Ohtsuka et al., 2008]. ZEB2 is a member of the family of the two-handed zinc finger/ homeodomain proteins containing an SMAD-binding domain (p.437–487), a homeodomain-like sequence (p.651–700), and two separate clusters of zinc fingers: an N-terminal domain (p.213–304) and a C-terminal domain (p.1001–1076) [Verschueren et al., 1999]. "
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    ABSTRACT: Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by moderate or severe intellectual disability, a characteristic facial appearance, microcephaly, epilepsy, agenesis or hypoplasia of the corpus callosum, congenital heart defects, Hirschsprung disease, and urogenital/renal anomalies. It is caused by de novo heterozygous loss of function mutations including nonsense mutations, frameshift mutations, and deletions in ZEB2 at 2q22. ZEB2 encodes the zinc finger E-box binding homeobox 2 protein consisting of 1,214 amino acids. Herein, we report 13 nonsense and 27 frameshift mutations from 40 newly identified MWS patients in Japan. Although the clinical findings of all the Japanese MWS patients with nonsense and frameshift mutations were quite similar to the previous review reports of MWS caused by nonsense mutations, frameshift mutations and deletions of ZEB2, the frequencies of microcephaly, Hirschsprung disease, and urogenital/renal anomalies were small. Patients harbored mutations spanning the region between the amino acids 55 and 1,204 in wild-type ZEB2. There was no obvious genotype-phenotype correlation among the patients. A transfection study demonstrated that the cellular level of the longest form of the mutant ZEB2 protein harboring the p.D1204Rfs*29 mutation was remarkably low. The results showed that the 3'-end frameshift mutation of ZEB2 causes MWS due to ZEB2 instability. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 04/2014; 164A(8). DOI:10.1002/ajmg.a.36551 · 2.16 Impact Factor
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    • "Since the first description by Mowat et al (1998), approximately 200 patients have been reported and over 100 mutations have been described (Dastot-Le Moal et al., 2007). The phenotype/genotype correlation for these mutations is very variable, not only for a given mutation (Cerruti-Mainardi et al., 2005; Zweier et al., 2003) but also within the same family (McGaughran et al., 2005). The syndrome has been identified in several ethnic groups (Dastot-Le Moal et al., 2007), with similar clinical features in all populations. "

    Neuroimaging - Clinical Applications, 03/2012; , ISBN: 978-953-51-0200-7
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    • "Based on these lines of evidence, germ-line mosaicism is the most consistent hypothesis to explain familial recurrence, as already proposed based on analogue mechanism demonstrated in other dominant diseases [McGaughran et al., 2005]. Zweier et al. [2005] demonstrated somatic mosaicism in a parent with mild clinical signs. "

    American Journal of Medical Genetics Part A 12/2008; 146A(23):3095-9. DOI:10.1002/ajmg.a.32568 · 2.16 Impact Factor
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