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.

Unique organization of the frontonasal ectodermal zone in birds and mammals

“…Microforms of HPE include midfacial hypoplasia, a single central incisor, and hypotelorism, while some individuals with mutations in HPE genes are clinically unaffected. However, there is no clear phenotype-genotype correlation that adequately explains the spectrum of phenotypes in patients with HPE (Marini et al, 2003; Ming and Muenke, 2002; Nanni et al, 1999; Roessler et al, 1996) indicating the multifactorial etiology of the disease. These observations inspired studies to identify multiple mutations in patients with HPE and correlate these mutations with severity of phenotype (Ming and Muenke, 2002).…”

New insights into craniofacial morphogenesis

“…A sonic boom One of the best studied craniofacial abnormalities is holoprosencephaly (HPE), a syndrome that is associated with perturbations in a handful of Shh-related genes Brown et al, 1998;Cole and Krauss, 2003;Cordero et al, 2004a;Gripp et al, 2000;Marini et al, 2003;Ming et al, 2002;Roessler et al, 1996;Roessler et al, 2003). At one end of the HPE spectrum, fetuses exhibit cyclopia, a condition characterized by a single, central eye and no discernable nose, but a relatively normal-looking middle and lower face (Chiang et al, 2001).…”

The mutational spectrum of holoprosencephaly-associated changes within theSHHgene in humans predicts loss-of-function through either key structural alterations of the ligand or its altered synthesis

“…Additionally, in many cases the molecular alteration presents as a familial form, often including many generations, where its clinically relevant phenotypic spectrum is highly variable between mutation carriers. Clinical findings can extend from cyclopia, at the severe extreme, to less severe conditions that include several types of recognizable microforms such as the solitary median maxillary central incisor syndrome (SMMCI; see Nanni et al, 2001; Marini et al, 2003; Garavelli et al, 2004; reviewed in El-Jaick et al, 2007a), or even incomplete penetrance of obligate mutation carriers. Mutations have also been detected in related pathway factors such as PTCH1 (Ming et al, 2001; MIM# 601309; HPE7, MIM# 610828), the transcription factor gene GLI2 (Roessler et al, 2005; MIM# 165230; HPE9, MIM# 610829) and the putative ligand transporter DISP1 (Roessler et al, 2009; MIM# 607502).…”