Epimutations of the IG-DMR and the MEG3-DMR at the 14q32.2 imprinted region in two patients with Silver-Russell Syndrome-compatible phenotype.
Epimutations of the IG-DMR and the MEG3-DMR at the 14q32.2 imprinted region in two patients with Silver-Russell Syndrome-compatible phenotype.
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DOI：
10.1038/ejhg.2014.234
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发表时间：
2015-08
期刊：
影响因子：
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通讯作者：
Ogata T
中科院分区：
文献类型：
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作者：
Kagami M;Mizuno S;Matsubara K;Nakabayashi K;Sano S;Fuke T;Fukami M;Ogata T
母亲单亲二体14 （UPD(14)mat）和影响14q32.2印迹区相关的（epi）遗传畸变导致临床可识别的疾病，最近被称为Temple综合征（TS）。TS的表型特征包括产前和产后生长衰竭、前额突出和进食困难，这些也在银罗素综合征（SRS）中发现。因此，我们研究了85名符合Netchine等人提出的SRS诊断标准的日本患者的UPD(14)mat和相关的（epi）遗传畸变与SRS发展的相关性，这些患者既没有H19-DMR的发生，也没有母亲单亲体7。焦磷酸测序在两个病例中发现了DLK1-MEG3基因间差异甲基化区（IG-DMR）和MEG3-DMR的低甲基化。在这两种情况下，微卫星分析都显示了14号染色体同源物的双亲遗传，没有证据表明存在涉及印迹区域的母体完全或节段性同染色体的体细胞镶嵌现象。FISH和阵列比较基因组杂交显示，在14q32.2印迹区没有两个DMRs的缺失，也没有明显的拷贝数改变。甲基化模式在其他6种与疾病相关的DMRs中明显正常。此外，一项全面的文献综述显示，尽管身体不对称是SRS的明显特征，但SRS和TS之间存在相当程度的表型重叠。结果表明，在这两例患者中，发生了影响IG-DMR和MEG3-DMR的变异，并暗示UPD(14)mat和相关的（epi）遗传畸变是SRS的一个罕见但重要的潜在因素。
Maternal uniparental disomy 14 (UPD(14)mat) and related (epi)genetic aberrations affecting the 14q32.2 imprinted region result in a clinically recognizable condition which is recently referred to as Temple Syndrome (TS). Phenotypic features in TS include pre- and post-natal growth failure, prominent forehead, and feeding difficulties that are also found in Silver–Russell Syndrome (SRS). Thus, we examined the relevance of UPD(14)mat and related (epi)genetic aberrations to the development of SRS in 85 Japanese patients who satisfied the SRS diagnostic criteria proposed by Netchine et al and had neither epimutation of the H19-DMR nor maternal uniparental disomy 7. Pyrosequencing identified hypomethylation of the DLK1-MEG3 intergenic differentially methylated region (IG-DMR) and the MEG3-DMR in two cases. In both cases, microsatellite analysis showed biparental transmission of the homologs of chromosome 14, with no evidence for somatic mosaicism with full or segmental maternal isodisomy involving the imprinted region. FISH and array comparative genomic hybridization revealed neither deletion of the two DMRs nor discernible copy number alteration in the 14q32.2 imprinted region. Methylation patterns were apparently normal in other six disease-associated DMRs. In addition, a thorough literature review revealed a considerable degree of phenotypic overlap between SRS and TS, although body asymmetry was apparently characteristic of SRS. The results indicate the occurrence of epimutation affecting the IG-DMR and the MEG3-DMR in the two cases, and imply that UPD(14)mat and related (epi)genetic aberrations constitute a rare but important underlying factor for SRS.