Beckwith–Wiedemann syndrome (BWS) presents with visceromegaly, macroglossia, tumor predisposition and other congenital abnormalities, and is usually associated with abnormalities of chromosome 11p15. A number of identical twin pairs, mostly female, have been reported to be discordant for BWS. We show here that the incidence of female monozygotic twins among patients with BWS is dramatically increased over that of the general population. A cluster of imprinted genes within 11p15 is thought to be coordinately regulated via the imprinted expression of KCNQ1OT1, which encodes an untranslated RNA. In skin fibroblasts from five monozygotic twin pairs discordant for BWS, each affected twin had an imprinting defect at KCNQ1OT1 on 11p15, whereas the unaffected twin did not. Five additional monozygotic twin pairs, for whom only blood was available, also displayed an imprinting defect at KCNQ1OT1. It is possible that discordance for BWS in MZ twins is due to unequal splitting of the inner cell mass during twinning, thereby causing differential maintenance of imprinting at KCNQ1OT1. Alternatively, we propose that KCNQ1OT1 is especially vulnerable to a loss of imprinting event, caused by a lack of maintenance DNA methylation at a critical stage of preimplantation development, and that this loss of imprinting predisposes to twinning as well as to discordance for BWS. These data underscore the importance of continued surveillance of children born following assisted reproductive technologies that impact the preimplantation embryo.

The Beckwith–Wiedemann syndrome (BWS) is characterized by somatic overgrowth and a predisposition to pediatric embryonal tumors. It is associated with genetic or epigenetic abnormalities in a cluster of imprinted genes found within a genomic region of approximately one megabase on human chromosome 11p15. Imprinted genes are expressed preferentially or exclusively from either the paternal or maternal allele. The 11p15 region is organized into two imprinted domains in which genomic imprinting is controlled by separate ‘imprinting control regions’. Twenty-five to 50% of BWS patients have biallelic rather than monoallelic expression of the insulin-like growth factor 2 (IGF2) gene. Another 50% of patients have an epigenetic mutation resulting in loss of imprinting of a transcript called KCNQ1OT1. Each of these genes resides in one of the two imprinted domains that appear to be subject to developmental dysregulation in BWS. In this review, we discuss the insights that the study of BWS have contributed to our understanding of the mechanisms of growth control, oncogenesis and genomic imprinting. Specifically, methylation and chromatin modification may coordinate the expression of closely linked imprinted genes. Finally, we discuss how knowledge of epigenetic mechanisms associated with the early stages of embryogenesis suggest caution in the current debate surrounding assisted reproductive and cloning technologies.

Dysregulation of imprinted genes on human chromosome 11p15 has been implicated in Beckwith–Wiedemann syndrome (BWS), an overgrowth syndrome associated with congenital malformations and tumor predisposition. The molecular basis of BWS is complex and heterogeneous. The syndrome is associated with alterations in two distinct imprinting domains on 11p15: a telomeric domain containing the H19 and IGF2 genes and a centromeric domain including the KCNQ1OT1 and CDKNIC genes. It has been postulated that disorders of imprinting in the telomeric domain are associated with overgrowth and cancer predisposition, whereas those in the centromeric domain involve malformations but not tumor development. In this study of 125 BWS cases, we confirm the association of tumors with constitutional defects in the 11p15 telomeric domain; six of 21 BWS cases with uniparental disomy (UPD) of 11p15 developed tumors and one of three of the rare BWS subtype with hypermethylation of the H19 gene developed tumors. Most importantly, we find that five of 32 individuals with BWS and imprinting defects in the centromeric domain developed embryonal tumors. Furthermore, the type of tumors observed in BWS cases with telomeric defects are different from those seen in BWS cases with defects limited to the centromeric domain. Whereas Wilms’ tumor was the most frequent tumor seen in BWS cases with UPD for 11p15 or H19 hypermethylation, none of the embryonal tumors withimprinting defects at KCNQ1OT1 was a Wilms’ tumor. This suggests that distinct tumor predisposition profiles result from dysregulation of the telomeric domain versus the centromeric domain and that these imprinting defects activate distinct genetic pathways for embryonal tumorigenesis.