Deciphering Epigenetic Backgrounds in a Korean Cohort with Beckwith–Wiedemann Syndrome

Abstract

Background: Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth disorder caused by genetic or epigenetic alterations at two imprinting centers (ICs) in the 11p15.5 region. Delineation of the molecular defects is important for prognosis and predicting familial recurrence. We evaluated epigenetic alterations and potential epigenotype-phenotype correlations in Korean children with BWS.Methods: Forty children with BWS with proven genetic or epigenetic defects in the 11p15.5 region were included. The phenotype was scored using the BWS consensus scoring system. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), bisulfite pyrosequencing, a single-nucleotide polymorphism microarray, and CDKN1C sequencing were used for confirmative diagnosis.Results: Patients met the criteria for genetic testing, with a mean clinical score of 5.4 ± 2.0. Methylation alterations were consistent between MS-MLPA and bisulfite pyrosequencing in all patients. Twenty-six patients (65.0%) had IC2 loss of methylation (IC2-LoM), 11 (27.5%) had paternal uniparental disomy (patUPD), and one (2.5%) had IC1 gain of methylation. Macroglossia and external ear anomalies were more common in IC2-LoM than in patUPD, and lateralized overgrowth was more common in patUPD than in IC2-LoM (all P < 0.05). Methylation levels at IC2 were inversely correlated with birth weight standard deviation score (r = -0.476, P = 0.014) and clinical score (r = -0.520, P = 0.006) in the IC2-LoM group.Conclusions: Comprehensive molecular analysis of the 11p15.5 region revealed epigenotype-phenotype correlations in our BWS cohort. Bisulfite pyrosequencing can help clarify epigenotypes. Methylation levels were correlated with fetal growth and clinical severity in patients with BWS.

Development of disease‐specific growth charts for Korean children with Beckwith–Wiedemann syndrome

“…The remaining 51 children (27 males and 24 females) with confirmed molecular defects in 11p15.5, were included in this retrospective study (Figure S1). Epimutations at the chromosome 11p15.5 imprinting region were confirmed in all patients using methylation‐specific multiplex ligation‐dependent probe amplification and bisulfite pyrosequencing analysis using leukocyte genomic DNA as previously described 5 . Anthropometric measurements, including height, weight, and head circumference, were performed every 6–12 months during the clinical visits.…”

“…Epimutations at the chromosome 11p15.5 imprinting region were confirmed in all patients using methylationspecific multiplex ligation-dependent probe amplification and bisulfite pyrosequencing analysis using leukocyte genomic DNA as previously described. 5 Anthropometric measurements, including height, weight, and head circumference, were performed every 6-12 months during the clinical visits. To ensure consistency, 25 measurements obtained during the first 12 months of life in 4 males and 4 females born prematurely (before gestational Week 37) were excluded from the analysis.…”

“…The underlying genetic or epigenetic defects in BWS occur within chromosome 11p15.5 region, which contains two imprinting center regions (ICRs; IC1 and IC2) that play critical roles in regulating the parent‐specific expression of genes involved in growth regulation 4 . Alterations in these regions lead to the dysregulation of growth‐related genes, such as CDKN1C and IGF2 , contributing to the distinct clinical features observed in BWS 3,5 …”

Bilateral Dimorphism of the Auricles in 18–20-year-old Girls

“…Например, синдромы трисомии 13 (Патау) и 18 (Эдвардса), а также синдромы Нунан и Смит-Лемли-Опица [19] связаны с «низкой посадкой» и деформированием УР. У пациентов с синдромом Дауна размеры УР меньше нормальных, в то время как мальформации УР тесно связаны с синдромом Беквита-Видемана [11]. Размеры и форма дольки УР также являются важными параметрами для хирургов при планировании и проведении оперативных вмешательств на УР с реконструктивной и/или эстетической целью [2].…”