(Epi)genetic profiling of extraembryonic and postnatal tissues from female monozygotic twins discordant for Beckwith–Wiedemann syndrome

Abstract

Background Beckwith–Wiedemann syndrome (BWS) is an overgrowth disorder caused by defects at the 11p15.5 imprinted region. Many cases of female monozygotic (MZ) twins discordant for BWS have been reported, but no definitive conclusions have been drawn regarding the link between epigenetic defects, twinning process, and gender. Here, we report a comprehensive characterization and follow‐up of female MZ twins discordant for BWS. Methods Methylation pattern at 11p15.5 and multilocus methylation disturbance (MLID) profiling were performed by pyrosequencing and MassARRAY in placental/umbilical cord samples and postnatal tissues. Whole‐exome sequencing was carried out to identify MLID causative mutations. X‐chromosome inactivation (XCI) was determined by HUMARA test. Results Both twins share KCNQ1OT1:TSS‐DMR loss of methylation (LOM) and MLID in blood and the epigenetic defect remained stable in the healthy twin over time. KCNQ1OT1:TSS‐DMRLOM was nonhomogeneously distributed in placental samples and the twins showed the same severely skewed XCI pattern. No MLID‐causative mutations were identified. Conclusion This is the first report on BWS‐discordant twins with methylation analyses extended to extraembryonic tissues. The results suggest that caution is required when attempting prenatal diagnosis in similar cases. Although the causative mechanism underlying LOM remains undiscovered, the XCI pattern and mosaic LOM suggest that both twinning and LOM/MLID occurred after XCI commitment.

Clinical and Molecular Diagnosis of Beckwith-Wiedemann Syndrome with Single- or Multi-Locus Imprinting Disturbance

“…We recently investigated a MZ female twin pair discordant for BWS by analyzing MLID and the XCI pattern. We found that the affected twin carried IC2 LOM and MLID in both blood and buccal swab, while the healthy twin presented IC2 LOM and MLID only in blood, probably as a consequence of placental vascular connections [ 11 ]. These results suggest a common pathomechanism leading to IC2 LOM and MLID that acts either after the twinning event and/or forces the segregation of the epimutated cells to one embryo.…”

“…These results suggest a common pathomechanism leading to IC2 LOM and MLID that acts either after the twinning event and/or forces the segregation of the epimutated cells to one embryo. Regarding the XCI pattern, since both twins presented the same skewed XCI, we hypothesized that the establishment of XCI precedes and may trigger IC2 LOM and MLID [ 11 ]. Interestingly, deviations from the random pattern of XCI has been already reported in non-X-linked diseases [ 98 ].…”

“…Moreover, the identification of a high incidence of female monozygotic (MZ) twins with discordant phenotypes and a high frequency of BWS among babies conceived by assisted reproductive technologies (ART), provide additional insights into the timing of imprint establishment during embryo development [ 9 , 10 , 11 ].…”

Characteristics Associated with Tumor Development in Individuals Diagnosed with Beckwith–Wiedemann Spectrum: Novel Tumor-(epi)Genotype-Phenotype Associations in the BWSp Population

“…The theory of diffused mosaicism was suggested by Cohen et al [29] and has been accepted by others [38,39]. Complementary to this theory, we recently proposed the theory of epigenetic burden to suggest potential phenotypic consequence of diffused epigenetic mosaicism in the context of IC2 LOM and BWSp [26].…”

Epigenetic mosaicism and cell burden in Beckwith–Wiedemann syndrome due to loss of methylation at imprinting control region 2

“…Diffused epigenetic mosaicism has been proposed to describe the phenotypic divergence that can occur between twins affected by BWSp ( Cohen et al 2019 ). More recently, case reports have provided support for this theory ( Fontana et al 2020 ; Sun et al 2021 ); however, no direct evidence demonstrating the tissue mosaicism exists to date.…”