Epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome
Epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome
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DOI：
10.1136/jmg.37.12.921
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发表时间：
2000-12-01
影响因子：
4
通讯作者：
Maher, ER
中科院分区：
文献类型：
--
作者：
Engel, JR;Smallwood, A;Maher, ER
Beckwith-Wiedemann综合征（BWS）是一种典型的印记疾病，由染色体11p15.5上的印记基因突变或表观遗传事件引起。因此，CDKN 1C的种系突变、单亲二体性（UPD）以及IGF 2和其他印记基因的印记丢失都与此有关。许多家族性BWS病例具有生殖系CDKN1C突变。然而，大多数BWS病例是散发性的，UPD或推定的印迹错误在这组中占主导地位。我们以前已经确定了一个亚组的散发病例与损失的印记（LOI）的IGF2和表观遗传沉默的H19提出的缺陷引起的远端11p15.5印记控制元件（指定BWSIC 1）。然而，许多散发性BWS患者在存在正常H19甲基化和表达模式的情况下显示双等位基因IGF2表达。这一证据和其他证据表明，在11p15.5存在另一个印记控制元件（BWSIC 2）。最近，我们发现BWS患者的一个亚组在IGF2和H19基因的KCNQ1基因着丝粒内的差异甲基化区域（KvDMR 1）有甲基化缺失（LOM）。我们现在已经分析了大量的散发病例，以确定BWS表观遗传异常的频率和表型相关性。在69例无UPD的散发性BWS中，35例（51%）通过Southern分析或基于PCR的新方法检测到KvDMR 1处的LOM。KvDMR1的LOM通常但并非总是与IGF2的LOI相关。在具有推定的BWSIC 1缺陷的BWS患者和具有KvDMR 1 LOM的病例中未检测到KvDMR 1 LOM。(that即推定的BWSIC 2缺陷）总是具有正常的H19甲基化模式。推定的BWSIC 2缺陷患者的外泌型发生率与生殖系CDKN1C突变患者无显著差异（分别为20/29和13/15），但显著高于推定的BWSIC 1缺陷患者（0/5，p = 0.007）和UPD患者（0/22，p
Beckwith-Wiedemann syndrome (BWS) is a model imprinting disorder resulting from mutations or epigenetic events involving imprinted genes at chromosome 11p15.5. Thus, germline mutations in CDKN1C, uniparental disomy (UPD), and loss of imprinting of IGF2 and other imprinted genes have been implicated. Many familial BWS cases have germline CDKN1C mutations. However, most BWS cases are sporadic and UPD or putative imprinting errors predominate in this group. We have identified previously a subgroup of sporadic cases with loss of imprinting (LOI) of IGF2 and epigenetic silencing of H19 proposed to be caused by a defect in a distal 11p15.5 imprinting control element (designated BWSIC1). However, many sporadic BWS patients show biallelic IGF2 expression in the presence of normal H19 methylation and expression patterns. This and other evidence suggested the existence of a further imprinting control element (BWSIC2) at 11p15.5. Recently, we showed that a subgroup of BWS patients have loss of methylation (LOM) at a differentially methylated region (KvDMR1) within the KCNQ1 gene centromeric to the IGF2 and H19 genes. We have now analysed a large series of sporadic cases to define the frequency and phenotypic correlates of epigenetic abnormalities in BWS. LOM at KvDMR1 was detected by Southern analysis or a novel PCR based method in 35 of 69 (51%) sporadic BWS without UPD. LOM at KvDMR1 was often, but not invariably associated with LOI of IGF2. KvDMR1 LOM, was not detected in BWS patients with putative BWSIC1 defects and cases with KvDMR1 LOM. (that is, putative BWSIC2 defects) invariably had a normal H19 methylation pattern. The incidence of exomphalos in putative BWSIC2 defect patients was not significantly different from that in patients with germline CDKN1C mutations (20/29 and 13/15 respectively), but was significantly greater than that in patients with putative BWSIC1 defects (0/5, p=0.007) and UPD (0/22, p