Department of Pediatrics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul, Korea.
Ann Lab Med. 2022 Nov 1;42(6):668-677. doi: 10.3343/alm.2022.42.6.668.
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.
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 sequencing were used for confirmative diagnosis.
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 <0.05). Methylation levels at IC2 were inversely correlated with birth weight standard deviation score (r=-0.476, =0.014) and clinical score (r=-0.520, =0.006) in the IC2-LoM group.
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.
贝克威思-威德曼综合征（BWS）是一种先天性过度生长障碍，由 11p15.5 区域两个印迹中心（IC）的遗传或表观遗传改变引起。明确分子缺陷对于预后和预测家族复发很重要。我们评估了韩国患有 BWS 的儿童的表观遗传改变和潜在的表型-基因型相关性。
纳入了 40 名患有 BWS 的儿童，这些儿童在 11p15.5 区域具有已知的遗传或表观遗传缺陷。使用 BWS 共识评分系统对表型进行评分。使用甲基化特异性多重连接依赖性探针扩增（MS-MLPA）、亚硫酸氢盐焦磷酸测序、单核苷酸多态性微阵列和测序进行确认诊断。
患者符合基因检测标准，平均临床评分为 5.4±2.0。在所有患者中，MS-MLPA 和亚硫酸氢盐焦磷酸测序的甲基化改变一致。26 名患者（65.0%）存在 IC2 去甲基化（IC2-LoM），11 名患者（27.5%）存在父源单亲二体（patUPD），1 名患者（2.5%）存在 IC1 甲基化增加。IC2-LoM 比 patUPD 更常见巨舌症和外耳异常，patUPD 比 IC2-LoM 更常见单侧过度生长（均<0.05）。在 IC2-LoM 组中，IC2 的甲基化水平与出生体重标准差评分（r=-0.476，=0.014）和临床评分（r=-0.520，=0.006）呈负相关。
对 11p15.5 区域的全面分子分析揭示了我们的 BWS 队列中的表型-基因型相关性。亚硫酸氢盐焦磷酸测序有助于阐明表型。BWS 患者的甲基化水平与胎儿生长和临床严重程度相关。
