Mowat-Wilson syndrome (MWS) is characterized by distinctive facial features; structural anomalies including Hirschsprung disease, genitourinary anomalies (particularly hypospadias in males), congenital heart defects (abnormalities of the pulmonary arteries and/or valves), agenesis or hypogenesis of the corpus callosum, and eye defects (microphthalmia and Axenfeld anomaly); and functional differences including moderate to severe intellectual disability, severe speech impairment with relative preservation of receptive language, seizures, growth retardation with microcephaly, and chronic constipation in those without Hirschsprung disease.
Mutations and deletions in the gene ZEB2 (also known as ZFHX1B or SIP-1) cause MWS. Sequence analysis detects mutations in approximately 81% of individuals; FISH detects large deletions encompassing all or part of ZEB2 in approximately 15% of persons; chromosomal rearrangements that disrupt the ZEB2 gene cause MWS in approximately 2% of individuals; and an additional 2% have intermediate-sized deletions that can be detected by techniques such as quantitative PCR, MLPA or gene-specific array GH.
Mowat-Wilson syndrome is typically the result of a de novo dominant mutation. When MWS results from a de novo mutation, the risk to the sibs of a proband is small. No individuals with MWS have been known to reproduce. Although the vast majority of MWS occurs as the result of a de novo mutation, molecular genetic testing can be used to evaluate a pregnancy at theoretically increased risk because of constitutional and/or germline mosaicism for a ZEB2 mutation in a clinically unaffected parent. Parents of an individual with MWS resulting from a structural unbalanced chromosome constitution (e.g., deletion, duplication) are at risk of having a balanced chromosome rearrangement. The risk to sibs of a proband with a structural unbalanced chromosome abnormality depends upon the chromosome findings in the parents. Prenatal diagnosis for pregnancies at increased risk because of parental balanced structural rearrangement is possible by chromosome analysis of fetal cells obtained by amniocentesis or chorionic villus sampling.