NSD1 mutations generate a genome-wide DNA methylation signature.
NSD1 mutations generate a genome-wide DNA methylation signature.
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DOI：
10.1038/ncomms10207
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发表时间：
2015-12-22
影响因子：
16.6
通讯作者：
Weksberg R
中科院分区：
文献类型：
--
作者：
Choufani S;Cytrynbaum C;Chung BH;Turinsky AL;Grafodatskaya D;Chen YA;Cohen AS;Dupuis L;Butcher DT;Siu MT;Luk HM;Lo IF;Lam ST;Caluseriu O;Stavropoulos DJ;Reardon W;Mendoza-Londono R;Brudno M;Gibson WT;Chitayat D;Weksberg R
Sotos综合征（SS）是研究表观遗传调控的重要人类模型系统;它是由组蛋白甲基转移酶（NSD 1）突变引起的过度生长/智力障碍综合征。由于分层表观遗传修饰通常是相互依赖的，我们提出致病性NSD 1突变对最稳定的表观遗传标记DNA甲基化（DNAm）具有全基因组影响。通过询问SS患者的DNAm，我们确定了一个全基因组的，高度显著的NSD 1 +/−特异性特征，该特征将致病性NSD 1突变与对照、良性NSD 1变异和临床重叠的韦弗综合征区分开来。SS和对照的独立队列的验证研究正确分配了100%的这些样本。这种高度特异性和敏感性的NSD 1 +/−特征包括在细胞形态发生和神经元分化中起作用的基因，反映了SS表型的主要特征。SS特异性全基因组DNAm改变的鉴定将有助于阐明SS的分子病理生理学和改进诊断测试的发展。 Sotos综合征是一种生长综合征，其特征是儿童期的提前生长、特征性面部外观和智力残疾。在这里，作者确定了一个全基因组DNA甲基化特征，可以准确诊断Sotos综合征，并将其与类似疾病区分开来。
Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1+/−-specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1+/− signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing. Sotos syndrome is an growth syndrome characterized by advanced growth in childhood, characteristic facial appearance and intellectual disability. Here the authors identify a genome-wide DNA methylation signature that accurately diagnoses Sotos Syndrome and distinguishes it from similar conditions.