Beckwith-Wiedemann syndrome

Abstract

Beckwith-Wiedemann syndrome (BWS) is a model disorder for the study of imprinting, growth dysregulation, and tumorigenesis. Unique observations in this disorder point to an important embryonic developmental window relevant to the observations of increased monozygotic twinning and an increased rate of epigenetic errors after subfertility/assisted reproduction.

Figure 1

(a) A 1-month-old boy with BWS showing macroglossia and umbilical hernia. (b) Later photograph, 1 year after tongue.

Figure 2

(a) Schematic representation of the chromosome 11p15.5 imprinted region that is functionally divided into two domains. In the distal domain 1 are two imprinted genes, H19 and insulin-like growth factor 2 (1GF2). IGF2 is a paternally expressed fetal growth factor and H19 is a noncoding RNA. The H19-associated imprinting center (IC1) is usually methylated on the paternal chromosome and unmethylated on the maternal chromosome. Normally, the H19 gene is expressed from the maternal allele and IGF2 from the paternal allele. Domain 2 contains several imprinted genes, including KCNQ1, KCNQ1OT1, and CDKN1C. A differentially methylated region (IC2) contains the promoter for KCNQ1OT1, a paternally expressed noncoding transcript that regulates in cis the expression of the maternally expressed imprinted genes in domain 2. Two examples of imprinting alterations leading to Beckwith–Wiedemann syndrome (BWS) are shown in (b1) and (b2). (b1) IC1 gain of methylation in BWS is found in ∼5% of patients and leads to biallelic expression of IGF2. (b2) Loss of methylation at the KvDMR differentially methylated region (IC2) is found in 50% of BWS patients. This epigenetic alteration leads to reduced expression of CDKN1C. Red corresponds to preferential maternal allelic expression, blue corresponds to preferential paternal allelic expression. Filled rectangles indicate expressed genes and empty rectangles indicate non-expressed gene. Lollipops correspond to methylated sites.

Figure 3

A clinical approach to testing for BWS.

Figure 4

Enrichment of epigenetic defects in Beckwith–Wiedemann (BWS). In the general population, loss of methylation (LOM) at KvDMR on chromosome 11p15.5 contributes to 50% of BWS cases, whereas in the BWS/ART population, LOM at KvDMR is found in ∼95% of cases. This represents a 1.9-fold enrichment of this epigenetic defect in the BWS/ART population.