Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome
Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome
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DOI：
10.1038/sj.ejhg.5201463
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发表时间：
2005-09-01
影响因子：
5.2
通讯作者：
Maher, ER
中科院分区：
文献类型：
--
作者：
Cooper, WN;Luharia, A;Maher, ER
beck - wiedemann综合征（BWS）是由11p15.5位点的印迹基因突变或表观遗传事件引起的。大多数BWS病例是散发的，单代二体（UPD）或推定的印记错误在这一群体中占主导地位。具有推测的印迹缺陷的偶发病例可细分为(a)由于远端11p15.5印迹控制元件（IC1）缺陷而导致的IGF2和H19的印迹缺失（LOI）和高甲基化和沉默，以及(b) KvDMR1、kcnq10ot1的LOI （LIT1）和IGF2的可变LOI缺失，其中在更近端印迹控制元件（IC2）存在缺陷。我们研究了200例分子遗传学诊断为BWS的患者的基因型/表观遗传型-表型相关性（16例CDKN1C突变，116例印迹中心2缺陷，14例印迹中心1缺陷，54例UPD）。半肥厚与UPD密切相关（P < 0.0001），畸形与IC2缺陷或CDKN1C突变相关，但与UPD或IC1缺陷无关（P < 0.0001）。比较出生体重百分位数时，IC1缺陷组明显重于CDKN1C突变或IC2缺陷组（P = 0.018）。UPD和IC1缺陷病例发生肿瘤的风险明显高于IC2缺陷和CDKN1C突变病例。Kaplan-Meier分析显示，所有患者5岁时发生肿瘤的风险为9%，但UPD亚组为24%。在IC2缺陷亚组中，Wilms肿瘤的风险似乎是最小的，并且似乎没有针对Wilms肿瘤的密集筛查。在UPD患者中，UPD扩展至WT1与肾肿瘤发生相关（P = 0.054）。这些发现表明，BWS代表了一系列疾病。分子亚型的鉴定可以更准确地预测预后，并加强对BWS儿童的管理和监测，从而可以将Wilms肿瘤和肝母细胞瘤的筛查重点放在那些风险最高的儿童身上。
Beckwith-Wiedemann Syndrome (BWS) results from mutations or epigenetic events involving imprinted genes at 11p15.5. Most BWS cases are sporadic and uniparental disomy (UPD) or putative imprinting errors predominate in this group. Sporadic cases with putative imprinting defects may be subdivided into (a) those with loss of imprinting (LOI) of IGF2 and H19 hypermethylation and silencing due to a defect in a distal 11p15.5 imprinting control element (IC1) and (b) those with loss of methylation at KvDMR1, LOI of KCNQ1OT1 (LIT1) and variable LOI of IGF2 in whom there is a defect at a more proximal imprinting control element (IC2). We investigated genotype/epigenotype-phenotype correlations in 200 cases with a confirmed molecular genetic diagnosis of BWS (16 with CDKN1C mutations, 116 with imprinting centre 2 defects, 14 with imprinting centre 1 defects and 54 with UPD). Hemihypertrophy was strongly associated with UPD (P < 0.0001) and exomphalos was associated with an IC2 defect or CDKN1C mutation but not UPD or IC1 defect (P < 0.0001). When comparing birth weight centile, IC1 defect cases were significantly heavier than the patients with CDKN1C mutations or IC2 defect (P = 0.018). The risk of neoplasia was significantly higher in UPD and IC1 defect cases than in IC2 defect and CDKN1C mutation cases. Kaplan-Meier analysis revealed a risk of neoplasia for all patients of 9% at age 5 years, but 24% in the UPD subgroup. The risk of Wilms' tumour in the IC2 defect subgroup appears to be minimal and intensive screening for Wilms' tumour appears not to be indicated. In UPD patients, UPD extending to WT1 was associated with renal neoplasia (P = 0.054). These findings demonstrate that BWS represents a spectrum of disorders. Identification of the molecular subtype allows more accurate prognostic predictions and enhances the management and surveillance of BWS children such that screening for Wilms' tumour and hepatoblastoma can be focused on those at highest risk.