Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, Ontario N6A5W9, Canada.
Department of Pathology and Laboratory Medicine, Western University, London, Ontario N6A3K7, Canada.
Hum Mol Genet. 2020 Sep 30;29(R1):R27-R32. doi: 10.1093/hmg/ddaa144.
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.
在过去的二十年中，疑似孟德尔神经发育障碍患者的基因检测范围和复杂性迅速扩大。然而，尽管基因组技术取得了进步，但仍有一半以上的患者无法进行基因诊断。表观基因组学，特别是基因组 DNA 甲基化谱，现在已知与越来越多的孟德尔疾病的潜在遗传缺陷有关。这些通常非常特异性和敏感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。除了基因组测序技术之外，增加诊断产量使表观基因组学迅速应用于临床，最近在临床诊断实验室中引入了 DNA 甲基化“EpiSign”分析。本文综述了 DNA 甲基化表观遗传特征分析在神经发育性孟德尔疾病患者中的原理、应用和局限性，并讨论了这一新兴诊断技术的临床意义。
