Clinical and Mutational Spectrum of Mowat–Wilson Syndrome

Abstract

Mowat–Wilson Syndrome is a recently delineated mental retardation syndrome usually associated with multiple malformations and a recognizable facial phenotype caused by defects of the transcriptional repressor ZFHX1B. To address the question of clinical and mutational variability, we analysed a large number of patients with suspected Mowat–Wilson Syndrome (MWS). Without prior knowledge of their mutational status, 70 patients were classified into “typical MWS”, “ambiguous” and “atypical” groups according to their facial phenotype. Using FISH, qPCR and sequencing, ZFHX1B deletions, splice site or truncating mutations were detected in all 28 patients classified as typical MWS. No ZFHX1B defect was apparent in the remaining 15 cases with ambiguous facial features or in the 27 atypical patients. Genotype–phenotype analysis confirmed that ZFHX1B deletions and stop mutations result in a recognizable facial dysmorphism with associated severe mental retardation and variable malformations such as Hirschsprung disease and congenital heart defects. Our findings indicate that structural eye anomalies such as microphthalmia should be considered as part of the MWS spectrum. We also show that agenesis of the corpus callosum and urogenital anomalies (especially hypospadias) are significant positive predictors of a ZFHX1B defect. Based on our observation of affected siblings and the number of MWS cases previously reported, we suggest a recurrence risk of around 1%. The lack of missense mutations in MWS and MWS-like patients suggests there may be other, as yet unrecognized phenotypes, associated with missense mutations of this transcription factor.

Introduction

In 1998, Mowat et al. [16] described a novel syndromic form of Hirschsprung disease (HSCR) associated with mental retardation, microcephaly, short stature and a facial appearance characterized by hypertelorism, pointed chin, prominent columella, broad, medial flared eyebrows and uplifted earlobes (MIM 235730). Shortly after, deletions and point mutations in the ZFHX1B gene (Fig. 1) were shown to underlie this condition [3], [21]. Further studies have demonstrated that HSCR is not an obligatory feature so that patients both with and without HSCR can be recognized by their distinctive facial gestalt [23], [25].

To date, 69 cases of MWS with nonsense or frameshift mutations, deletions or translocations have been published. No obvious genotype–phenotype correlation has been defined except for those two very large deletions [12], [26] associated with an exceptionally severe course [1], [3], [4], [8], [11], [12], [13], [17], [18], [21], [22], [23], [25], [26]. These observations led to the assumption of ZFHX1B haploinsufficiency as the underlying pathogenic mechanism in Mowat–Wilson Syndrome. Since no ZFHX1B missense mutation has yet been reported, we hypothesized that patients with atypical MWS phenotypes might harbour non-truncating ZFHX1B mutations such as the 3 bp inframe deletion described by Yoneda et al. [24] in a patient showing only late diagnosed megacolon and mild retardation with non-specific facial features.

To address the question of the full spectrum of clinical and mutational variability, we analysed 70 patients with clinical features of Mowat–Wilson Syndrome for deletions and mutations in ZFXH1B.