The breadth and complexity of genetic testing in patients with suspected Mendelian neurodevelopmental disorders has rapidly expanded in the past two decades. However, in spite of advances in genomic technologies, genetic diagnosis remains elusive in more than half of these patients. Epigenomics, and in particular genomic DNA methylation profiles, are now known to be associated with the underpinning genetic defects in a growing number of Mendelian disorders. These often highly specific and sensitive molecular biomarkers have been used to screen these patient populations, resolve ambiguous clinical cases and interpret genetic variants of unknown clinical significance. Increasing the diagnostic yield beyond genomic sequencing technologies has rapidly propelled epigenomics to clinical utilization, with recent introduction of DNA methylation ‘EpiSign’ analysis in clinical diagnostic laboratories. This review provides an overview of the principles, applications and limitations of DNA methylation episignature analysis in patients with neurodevelopmental Mendelian disorders, and discusses clinical implications of this emerging diagnostic technology.

中文翻译：

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基因组变异的功能注释：神经发育孟德尔疾病中的 DNA 甲基化表观特征。

在过去的二十年里，对疑似孟德尔神经发育障碍患者进行基因检测的广度和复杂性迅速扩大。然而，尽管基因组技术取得了进步，但这些患者中有一半以上的基因诊断仍然难以捉摸。现在已知表观基因组学，特别是基因组 DNA 甲基化谱，与越来越多的孟德尔疾病的基础遗传缺陷有关。这些通常具有高度特异性和敏感性的分子生物标志物已被用于筛选这些患者群体、解决模棱两可的临床病例并解释具有未知临床意义的遗传变异。提高基因组测序技术以外的诊断产量已迅速将表观基因组学推向临床应用，随着最近在临床诊断实验室中引入 DNA 甲基化“EpiSign”分析。本综述概述了 DNA 甲基化表观特征分析在神经发育孟德尔疾病患者中的原理、应用和局限性，并讨论了这种新兴诊断技术的临床意义。