Author:

Keywords:

zfhx1b, mowat-wilson, parental mosaicism, microphthalmia, hscr, corpus callosum, hypospadias, mental retardation, smad-interacting protein-1, characteristic facial features, mental retardation syndrome, box 1b gene, hirschsprung-disease, deletions, sip1, delineation, expression, Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, ZFHX1B, Mowat-Wilson, HSCR, SMAD-INTERACTING PROTEIN-1, CHARACTERISTIC FACIAL FEATURES, MENTAL RETARDATION SYNDROME, BOX 1B GENE, HIRSCHSPRUNG-DISEASE, DELETIONS, SIP1, DELINEATION, EXPRESSION, Abnormalities, Multiple, Adolescent, Adult, Base Sequence, Child, Child, Preschool, Codon, Terminator, DNA, DNA Mutational Analysis, Female, Genotype, Homeodomain Proteins, Humans, Infant, Intellectual Disability, Male, Molecular Sequence Data, Mutation, Phenotype, RNA Splicing, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Sequence Deletion, Syndrome, Zinc Finger E-box Binding Homeobox 2, 0604 Genetics, 1103 Clinical Sciences, 3105 Genetics, 3202 Clinical sciences

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 ZFHXIB. 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, ZFHXIB deletions, splice site or truncating mutations were detected in all 28 patients classified as typical MWS. No ZFHXIB defect was apparent in the remaining 15 cases with ambiguous facial features or in the 27 atypical patients. Genotype-phenotype analysis confirmed that ZFHXIB 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 ZFHXIB 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. (c) 2005 Elsevier SAS. All rights reserved.