title: Ocular coloboma and high myopia with Hirschsprung disease associated with a novel ZFHX1B missense mutation and trisomy 21.
abstract: Syndromic Hirschsprung disease has been associated with mutations in ZFHX1B, a Smad-interacting transcriptional repressor protein. Tissue in situ hybridization has demonstrated strong expression of ZFHX1B in the developing eye, suggesting that some mutations in this gene may cause visual loss. However, none of the reported mutations have been associated with an ocular phenotype. We describe a patient with Down syndrome and Hirschsprung disease with high myopia and ocular coloboma affecting the iris and retina. In addition to trisomy 21, a novel, de novo heterozygous A to G transition in exon 8 of the ZFHX1B gene was identified, which results in a R953G amino acid substitution. This abnormality was not seen in a screen of 200 chromosomes from ethnically matched, normal controls. The arginine residue at position 953 is an extremely conserved amino acid throughout evolution. This is the first report associating Hirschsprung disease and severe eye defects with a specific genetic mutation and is the first report of a mutation in ZFHX1B causing a developmental ocular anomaly.
authors.affiliation: Department of Cell and Molecular Biology, Faculty of Medicine, Imperial College London, United Kingdom. c.gregory-evans@imperial.ac.uk
authors.forename: C Y
authors.initials: CY
authors.lastname: Gregory-Evans
authors.forename: H
authors.initials: H
authors.lastname: Vieira
authors.forename: R
authors.initials: R
authors.lastname: Dalton
authors.forename: G G W
authors.initials: GG
authors.lastname: Adams
authors.forename: A
authors.initials: A
authors.lastname: Salt
authors.forename: K
authors.initials: K
authors.lastname: Gregory-Evans
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D002648:Child; D003103:Coloboma / Q000473:pathology; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D004314:Down Syndrome / Q000473:pathology*; D005128:Eye Diseases / Q000473:pathology*; D005260:Female; D006627:Hirschsprung Disease / Q000473:pathology*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007621:Karyotyping; D008297:Male; D020125:Mutation, Missense; D009216:Myopia / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics*; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D018398:Homeodomain Proteins; D012097:Repressor Proteins; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D004247:DNA