Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Hum Mutat. 2011 Oct;32(10):1171-82. doi: 10.1002/humu.21558. Epub 2011 Sep 8.
The imprinted 11p15 region is organized in two domains, each of them under the control of its own imprinting control region (ICR1 for the IGF2/H19 domain and ICR2 for the KCNQ1OT1/CDKN1C domain). Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith-Wiedemann (BWS) and the Silver-Russell (SRS) syndromes. Various 11p15 genetic and epigenetic defects have been demonstrated in BWS and SRS. Among them, isolated DNA methylation defects account for approximately 60% of patients. To investigate whether cryptic copy number variations (CNVs) involving only part of one of the two imprinted domains account for 11p15 isolated DNA methylation defects, we designed a single nucleotide polymorphism array covering the whole 11p15 imprinted region and genotyped 185 SRS or BWS cases with loss or gain of DNA methylation at either ICR1 or ICR2. We describe herein novel small gain and loss CNVs in six BWS or SRS patients, including maternally inherited cis-duplications involving only part of one of the two imprinted domains. We also show that ICR2 deletions do not account for BWS with ICR2 loss of methylation and that uniparental isodisomy involving only one of the two imprinted domains is not a mechanism for SRS or BWS.
印记的 11p15 区域分为两个结构域，每个结构域都由其自身的印记控制区（IGF2/H19 结构域的 ICR1 和 KCNQ1OT1/CDKN1C 结构域的 ICR2）控制。11p15 印记的破坏会导致两种具有相反表型的胎儿生长障碍：贝克威思-威德曼（BWS）和西尔弗-拉塞尔（SRS）综合征。在 BWS 和 SRS 中已经证明了各种 11p15 遗传和表观遗传缺陷。其中，大约 60%的患者存在孤立的 DNA 甲基化缺陷。为了研究仅涉及两个印记结构域之一的部分的隐匿性拷贝数变异（CNVs）是否会导致 11p15 孤立的 DNA 甲基化缺陷，我们设计了一种覆盖整个 11p15 印记区域的单核苷酸多态性微阵列，并对 185 例在 ICR1 或 ICR2 处发生 DNA 甲基化缺失或获得的 SRS 或 BWS 病例进行了基因分型。我们在此描述了 6 例 BWS 或 SRS 患者中涉及两个印记结构域之一的部分的新型小增益和小缺失 CNVs，包括仅涉及两个印记结构域之一的母系顺式重复。我们还表明，ICR2 缺失不能解释 ICR2 甲基化缺失的 BWS，并且仅涉及两个印记结构域之一的单亲二体性不是 SRS 或 BWS 的机制。
