Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase 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.

中文翻译：

---

EZH2的DNA甲基化签名在功能上对三个PRC2复杂基因中的序列变异进行分类。

Weaver综合症（WS）是一种过度生长/智力残疾综合症（OGID），由组蛋白甲基转移酶EZH2中的致病变异引起，该酶编码Polycomb Repressed Complex-2（PRC2）的核心成分。使用187名OGID和969名对照受试者的全基因组DNA甲基化（DNAm）数据，我们显示EZH2中的致病性变体产生了高度特异性和敏感的DNAm签名，反映了WS的表型。此签名可用于区分功能丧失与功能获得错义变体，并检测体细胞镶嵌。我们还显示，该签名可以准确地对EED和SUZ12中的序列变体进行分类，而EED和SUZ12编码PRC2的两个其他核心组件，并预测未诊断的OGID个体中的致病性变体。