Molecular genetics of Beckwith-Wiedemann

Eamonn Maher
University of Birmingham Medical School

BWS is a model imprinting disorder resulting from mutations or epigenetic events involving imprinted genes at chromosome 11p15.5. Thus germline mutations in CDKN1C, uniparental disomy (UPD) and loss of imprinting of IGF2 and other imprinted genes have been implicated. Many (40%) familial BWS cases have germline CDKN1C mutations. However, most BWS cases are sporadic and UPD or putative imprinting errors predominate in this group. Sporadic cases with putative imprinting defects may be subdivided into (a) those with H19 hypermethylation and silencing and loss of imprinting (LOI) of IGF2 in whom it is postulated that there is a defect in a distal 11p15.5 imprinting control element (designated BWSIC1) and (b) those with loss of methylation at KvDMR1, LOI of the LIT1 transcript and variable LOI of IGF2 in whom it is postulated that there is a defect at a more proximal imprinting control element (BWSIC2). Phenotypic similarities and differences between different molecular subgroups of BWS patients suggest that although particular aspects of the BWS phenotype may be preferentially linked to specific genes, the imprinted gene products which determine the BWS phenotype act in related biochemical pathways.