Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Am J Med Genet A. 2010 Feb;152A(2):347-55. doi: 10.1002/ajmg.a.33204.
Russell-Silver syndrome (RSS) is a heterogeneous disorder associated with pre- and post-natal growth restriction and relative macrocephaly. Involvement of imprinted genes on both chromosome 7 and 11p15.5 has been reported. To further characterize the role of epimutations in RSS we evaluated the methylation status at both 11p15.5 imprinting control regions (ICRs): ICR1 associated with H19/IGF2 expression and ICR2 (KvDMR1) associated with CDKN1C expression in a series of 35 patients with RSS. We also evaluated methylation at the promoter regions of other imprinted genes involved in growth such as PLAGL1 (6q24), GCE (7q21), and PEG10 (7q21) in this series of 35 patients with RSS. Thirteen of the 35 patient samples, but none of 22 controls, showed methylation levels at ICR1 that were more than 2 SD below the mean for controls. Three RSS patients were highly methylated at the SCGE promoter, all of which were diagnosed with upd(7)mat. To identify further potential global methylation changes in RSS patients, a subset of 22 patients were evaluated at 1505 CpG sites by the Illumina GoldenGate methylation array. Among the few CpG sites displaying a significant difference between RSS patients and controls, was a CpG associated with the H19 promoter. No other sites associated with known imprinted genes were identified as abnormally methylated in RSS patients by this approach. While the association of hypomethylation of the H19/IGF2 ICR1 is clear, the continuous distribution of methylation values among the patients and controls complicates the establishment of clear cut-offs for clinical diagnosis.
Russell-Silver 综合征（RSS）是一种与产前和产后生长受限及相对大头有关的异质性疾病。据报道，7 号和 11p15.5 染色体上的印迹基因均有涉及。为了进一步研究 RSS 中表观遗传突变的作用，我们评估了 35 例 RSS 患者中 11p15.5 印迹控制区（ICR）的甲基化状态：与 H19/IGF2 表达相关的 ICR1 和与 CDKN1C 表达相关的 ICR2（KvDMR1）。我们还在这 35 例 RSS 患者中评估了其他参与生长的印迹基因启动子区域的甲基化情况，如 PLAGL1（6q24）、GCE（7q21）和 PEG10（7q21）。在这 35 例患者样本中，有 13 例但对照组无一例的 ICR1 甲基化水平低于对照组平均值的 2 个标准差以上。3 例 RSS 患者在 SCGE 启动子上高度甲基化，所有这些患者均被诊断为 upd(7)mat。为了在 RSS 患者中进一步确定潜在的全局甲基化变化，我们在 22 例患者的亚集中通过 Illumina GoldenGate 甲基化阵列评估了 1505 个 CpG 位点。在 RSS 患者和对照组之间显示出显著差异的少数 CpG 位点中，有一个与 H19 启动子相关的 CpG 位点。通过这种方法，没有发现其他与已知印迹基因相关的位点在 RSS 患者中异常甲基化。虽然 H19/IGF2 ICR1 的低甲基化是明确的，但患者和对照组之间甲基化值的连续分布使建立明确的临床诊断界限变得复杂。
