Abstract
ABSTRACTBeckwith–Wiedemann syndrome (BWS) is a complex imprinting disorder involving fetal overgrowth and placentomegaly, and is associated with a variety of genetic and epigenetic mutations affecting the expression of imprinted genes on human chromosome 11p15.5. Most BWS cases are linked to loss of methylation at the imprint control region 2 (ICR2) within this domain, which in mice regulates the silencing of several maternally expressed imprinted genes. Modelling this disorder in mice is confounded by the unique embryonic requirement for Ascl2, which is imprinted in mice but not in humans. To overcome this issue, we generated a novel model combining a truncation of distal chromosome 7 allele (DelTel7) with transgenic rescue of Ascl2 expression. This novel model recapitulated placentomegaly associated with BWS, but did not lead to fetal overgrowth.
Highlights
Beckwith–Wiedemann syndrome (BWS; MIM #130650) is a complex imprinting disorder associated with a range of growth and developmental phenotypes, including overgrowth, macroglossia, abdominal wall defects and an increased frequency of childhood tumours (Brioude et al, 2018; Lapunzina, 2005; Weksberg et al, 2010)
The placentomegaly of DelTel7BAC conceptuses was consistent with BWS, we did not recapitulate fetal overgrowth, which was previously considered a defining characteristic of BWS
Fetal overgrowth was apparent at E15.5 and E18.5, it was absent at birth
Summary
Beckwith–Wiedemann syndrome (BWS; MIM #130650) is a complex imprinting disorder associated with a range of growth and developmental phenotypes, including overgrowth, macroglossia, abdominal wall defects and an increased frequency of childhood tumours (Brioude et al, 2018; Lapunzina, 2005; Weksberg et al, 2010). BWS may be diagnosed on presentation with two major criteria and at least one ‘minor’ criterion, including placental defects, placentomegaly, neonatal hypoglycaemia and cardiomegaly (Õunap, 2016; Weksberg et al, 2010). A recent Consensus Statement proposes a re-evaluation of diagnostic criteria, describing several cardinal features (including macroglossia, lateralised overgrowth and placental mesenchymal dysplasia) alongside additional suggestive features The majority of cases occur sporadically, while ∼15% are inherited, for instance via loss of a functional maternal CDKN1C allele (Weksberg et al, 2010, 2005, 2003)
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