Molecular biology of Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with a predisposition to embryonal tumors, most commonly Wilms' (WT). Overlapping clinical phenotypes are seen in two other disorders, Simpson-Golabi-Behmel syndrome (SGBS) and Perlman syndrome (PS). BWS is a genetically heterogeneous disorder most often associated with normal chromosomes and a negative family history. However, autosomal dominant transmission of BWS is reported, as are chromosome 11p15.5 abnormalities, uniparental paternal disomy (UPD) of chromosome 11p15.5, and altered expression of the imprinted gene insulin-like growth factor 2 (IGF2) from the normally repressed maternal allele. Crucial to our understanding of the large variety of genetic presentations in BWS is the concept of genomic imprinting, a process in which gene expression specific to parent-of-origin is observed. The current genetic and molecular data for BWS are best explained by a model assuming an imprinted domain for 11p15.5, whereby altered expression of one or more genes in this region contributes to the BWS phenotype. In this model, a defined chromatin structure is reflected in coordinated control of multiple genes in the domain, as well as specific patterns of replication timing and gene expression. Data supporting this viewpoint include the maternally derived 11p15.5 translocation breakpoints associated with BWS, and the recent finding that the normally asynchronous pattern of replication timing for the imprinted gene IGF2 can be disrupted, shifted by a BWS-associated translocation 400 kh from IGF2. As we unravel the molecular basis of the different BWS patient subgroups, we will achieve a better understanding of this overgrowth syndrome and its relationship to WT.