title: Previously undescribed nonsense mutation in SHH caused autosomal dominant holoprosencephaly with wide intrafamilial variability.
abstract: Holoprosencephaly (HPE) is the most common developmental defect of the forebrain and midface in humans, with a frequency of 1/16,000 live births. Different genes are implicated in the pathogenesis of HPE; these include SHH, ZIC2, SIX3, TGIF, and human DKK1. We describe here a family with recurrence of autosomal dominant HPE in different members showing a wide clinical variability. The mother presents a single central maxillary incisor and mild hypotelorism as signs of the diseases, while three of her sons were affected by HPE. By direct sequencing and restriction analysis of exon 2 of the SHH gene, we have identified a previously undescribed nonsense mutation at codon 128 (W128X). The identification of this mutation allowed us to give a prenatal diagnosis in this family and confirms a wide intrafamilial variability in the phenotypic spectrum.
authors.affiliation: Laboratorio di Genetica Molecolare, Istituto G Gaslini, Genova, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Marini
authors.forename: Roberto
authors.initials: R
authors.lastname: Cusano
authors.forename: Pierangela
authors.initials: P
authors.lastname: De Biasio
authors.forename: Francesco
authors.initials: F
authors.lastname: Caroli
authors.forename: Margherita
authors.initials: M
authors.lastname: Lerone
authors.forename: Margherita
authors.initials: M
authors.lastname: Silengo
authors.forename: Roberto
authors.initials: R
authors.lastname: Ravazzolo
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
authors.forename: Gianni
authors.initials: G
authors.lastname: Camera
mesh_terms: D000022:Abortion, Spontaneous; D001483:Base Sequence; D018389:Codon, Nonsense; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005192:Family Health; D017809:Fatal Outcome; D005260:Female; D005313:Fetal Death; D005799:Genes, Dominant / Q000235:genetics; D053823:Hedgehog Proteins; D016142:Holoprosencephaly / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D010375:Pedigree; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D053823:Hedgehog Proteins; C509239:SHH protein, human; D015534:Trans-Activators; D004247:DNA