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.