Media type: E-Article Title: Previously undescribed nonsense mutation in SHH caused autosomal dominant holoprosencephaly with wide intrafamilial variability Contributor: Marini, Monica; Cusano, Roberto; De Biasio, Pierangela; Caroli, Francesco; Lerone, Margherita; Silengo, Margherita; Ravazzolo, Roberto; Seri, Marco; Camera, Gianni imprint: Wiley, 2003 Published in: American Journal of Medical Genetics Part A Language: English DOI: 10.1002/ajmg.a.10163 ISSN: 1552-4825; 1552-4833 Keywords: Genetics (clinical) ; Genetics Origination: Footnote: Description: <jats:title>Abstract</jats:title><jats:p>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 <jats:italic>SHH, ZIC2, SIX3, TGIF</jats:italic>, and human <jats:italic>DKK1</jats:italic>. 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 <jats:italic>SHH</jats:italic> 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 variabilty in the phenotypic spectrum. © 2003 Wiley‐Liss, Inc.</jats:p>