Clinical and molecular genetic features of Beckwith-Wiedemann syndrome associated with assisted reproductive technologies
Clinical and molecular genetic features of Beckwith-Wiedemann syndrome associated with assisted reproductive technologies
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DOI：
10.1093/humrep/den406
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发表时间：
2009-03-01
影响因子：
6.1
通讯作者：
Maher, Eamonn R.
中科院分区：
文献类型：
--
作者：
Lim, Derek;Bowdin, Sarah C.;Maher, Eamonn R.
Beckwith-Wiedemann综合征（BWS）是一种典型的印记疾病，由11p15.5印记基因的突变或表观遗传事件引起。大多数BWS病例是散发性的，由涉及两个11p15.5印迹控制区（IC 1和IC 2）之一的印迹错误（表突变）引起。以前，我们和其他人报道了散发性BWS与辅助生殖技术（ART）之间的关系。在这项研究中，我们比较了ART（IVF和ICSI）和非ART儿童散发性BWS的临床表型和分子特征。共有25例ART后BWS患者被确定（IVF后12例，ICSI后13例）。分子遗传学分析显示25名受试儿童中有24名存在IC 2表型突变（KvDMR 1甲基化丢失）。将ART后BWS儿童的临床特征与非ART BWS和IC 2缺陷儿童的临床特征进行比较，发现外泌瘤的频率较低（43 vs 69%，P = 0.029），肿瘤形成的风险较高（2例，P = 0.0014）。由于11p15.5以外的印迹控制区域的甲基化缺失可能会改变具有IC 2表型突变的BWS患者的表型，我们研究了ART后和非ART BWS IC 2病例中6 q24，7 q32和15 q13的差异甲基化区域（DMR）（n = 55）。在这些DMR中，37.5%的ART和6.4%的非ART BWS IC 2缺陷病例发生了母体等位基因甲基化丢失。因此，更广泛的DMR低甲基化是更频繁的，但不排除后ART BWS.These研究结果提供了进一步的证据，ART可能与干扰正常的基因组印记在一个子集的儿童。
Beckwith-Wiedemann syndrome (BWS) is a model imprinting disorder resulting from mutations or epigenetic events affecting imprinted genes at 11p15.5. Most BWS cases are sporadic and result from imprinting errors (epimutations) involving either of the two 11p15.5 imprinting control regions (IC1 and IC2). Previously, we and other reported an association between sporadic BWS and assisted reproductive technologies (ARTs).In this study, we compared the clinical phenotype and molecular features of ART (IVF and ICSI) and non-ART children with sporadic BWS. A total of 25 patients with post-ART BWS were ascertained (12 after IVF and 13 after ICSI).Molecular genetic analysis revealed an IC2 epimutations (KvDMR1 loss of methylation) in 24 of the 25 children tested. Comparison of clinical features of children with post-ART BWS to those with non-ART BWS and IC2 defects revealed a lower frequency of exomphalos (43 versus 69%, P = 0.029) and a higher risk of neoplasia (two cases, P = 0.0014). As loss of methylation at imprinting control regions other than 11p15.5 might modify the phenotype of BWS patients with IC2 epimutations, we investigated differentially methylated regions (DMRs) at 6q24, 7q32 and 15q13 in post-ART and non-ART BWS IC2 cases (n = 55). Loss of maternal allele methylation at these DMRs occurred in 37.5% of ART and 6.4% of non-ART BWS IC2 defect cases. Thus, more generalized DMR hypomethylation is more frequent, but not exclusive to post-ART BWS.These findings provide further evidence that ART may be associated with disturbed normal genomic imprinting in a subset of children.