DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes
DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes
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DOI：
10.1016/j.ajhg.2020.03.008
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发表时间：
2020-05-07
影响因子：
9.8
通讯作者：
Weksberg, Rosanna
中科院分区：
文献类型：
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作者：
Choufani, Sanaa;Gibson, William T.;Weksberg, Rosanna
Weaver综合征（WS）是一种过度生长/智力残疾综合征（OGID），由组蛋白甲基转移酶EZH2的致病性变异引起，EZH2编码Polycomb抑制复合物-2 （PRC2）的核心成分。利用187名OGID患者和969名对照者的全基因组DNA甲基化（DNAm）数据，我们发现EZH2的致病变异产生了一个高度特异性和敏感性的DNAm特征，反映了WS的表型。这种特征可以用来区分功能丧失和功能获得错义变异，并检测体细胞嵌合现象。我们还发现，该标记可以准确地分类编码PRC2另外两个核心成分的EED和SUZ12的序列变异，并预测未确诊的OGID个体中是否存在致病变异。对EZH2、EED和SUZ12序列变异进行诊断分类的功能相关特征的发现，支持了将DNAm特征应用于诊断和转化研究的新兴范式转变。
Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyl-transferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.