title: Novel Zeb2 gene variation in the Mowat Wilson syndrome (MWS).
abstract: BACKGROUND
  Mowat Wilson syndrome (MWS) is an uncommon association of Hirschsprung's disease (HSCR). Phenotypic features may develop with time, causing initial difficulties in diagnosis. MWS results from haploinsufficiency of the Zinc finger E-box-binding homeobox 2 (ZEB2) gene, and molecular diagnosis of ZEB2 mutation is required to confirm the diagnosis. We report the first confirmed cases of MWS in three children with the typical facial features, mental retardation, absent corpus callosum, epilepsy, and HSCR and novel Zeb2 variations on DNA analysis.
  
  
  METHODS
  Clinical features were monitored. DNA extracted from peripheral blood was subjected to bidirectional sequencing analysis following PCR DNA amplification. ZEB2 gene results were compared to the ZEB2 reference sequence (ENS00000169554) for variation. Bioinformatic investigation of novel gene variants was via the "Blastx" program function available via the National Center for Biotechnology Information (http://www.bioinfo.org/NPInter/blast/blast_link.cgi).
  
  
  RESULTS
  Clinical follow-up showed that the phenotypic features were not all present at birth but developed with time in 2 surviving patients. Several Zeb2 variations were detected in the promoter region of the ZEB2 gene of which 2 were novel (-56A/T 1174 11A/12A). In addition, a novel heterozygous single nucleotide insertion in exon 2 of ZEB2 in one patient results in a frameshift causing deletion of the first 8 amino acids of the ZEB2 protein and an alteration of amino acids 9 (G9A), 11 (R11G), and 12 (C12A). In the third patient, a novel single nucleotide deletion exon 8 (1784delC Het) results in a frameshift at amino acid 595 of translated protein. This shortens protein from 1214 to 594 amino acids and affects the functionality of the critical ZEB2 protein.
  
  
  CONCLUSIONS
  MWS is an important link to recognise clinically. It underlines the functionality of the Zeb2 gene in certain syndromic Hirschsprung's disease. These variations probably contribute to the clinical features of the Mowat Wilson phenotype in Hirschsprung's disease but should be confirmed in further research.
authors: Division of Paediatric Surgery, University of Stellenbosch, Tygerberg, Western Cape Tygerberg. Electronic address: swm@sun.ac.za.
authors: Sam W
authors: SW
authors: Moore
authors: Division of Clinical Genetics, University of Cape Town, Western Cape Red Cross Children's.
authors: Karen
authors: K
authors: Fieggen
authors: Department Genetics, Division Human Genetics, University of Pretoria, Gauteng.
authors: Engela
authors: E
authors: Honey
authors: Division of Paediatric Surgery, University of Stellenbosch, Tygerberg, Western Cape Tygerberg.
authors: Monique
authors: M
authors: Zaahl
mesh_terms: D002648:Child; D002675:Child, Preschool; D019066:Facies; D005260:Female; D005819:Genetic Markers; D006627:Hirschsprung Disease / Q000175:diagnosis / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics*; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D005819:Genetic Markers; D018398:Homeodomain Proteins; D012097:Repressor Proteins; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2
keywords: Africa; Familial; Genetics; Hirschsprung’s disease; Mowat Wilson; ZEB2 gene