Molecular analysis of patients with Wiedemann-Beckwith syndrome I. Gene dosage on the short arm of chromosome 11

Publisher Website
Google Scholar
Abstract
Wiedemann-Beckwith syndrome (WBS) is characterised by a specific group of congenital malformations associated with an increased concurrent risk for development of a defined group of childhood neoplasms. The mode of inheritance is complex, but recently compiled family data suggest that it is an autosomal dominant trait of varying expression. It has previously been suggested that major rearrangements on the short arm of chromosome 11 may be involved in the aetiology of the disease, particularly in the region of the insulin like growth factor II (IGF-II) gene (11p15.5). This gene is thought to be parentally imprinted in the mouse and it has been suggested that in the human, duplication of the non-imprinted locus in WBS patient might lead to diploid expression of the gene and consequent general hyperplasia. This model predicts that there should be both frequent and parental origin specific duplication of the IGF-II gene in the patients. It was the aim of this study to examine the IGF-II locus and its surrounding chromosomal environment for such lesions in a large number of WBS patients. Using restriction fragment length polymorphism analysis for four linked markers on 11p and genomic clones internal to the IGF-II locus we could find no evidence of alteration or amplification of this area in any of the 11 patients investigated. In one patient who developed a Wilms tumour we could find no evidence for loss of any material on the short arm of chromosome 11 as reported previously. We conclude that amplification of genes on the short arm of chromosome 11 is not a frequent occurrence in WBS and certainly not a prerequisite, leaving open the possibility that mutations in unknown transacting factors might affect the expression of IGF-II in these patients in the absence of lesions in the gene itself.