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The omics era: a nexus of untapped potential for Mendelian chromatinopathies
Human Genetics ( IF 3.8 ) Pub Date : 2023-04-28 , DOI: 10.1007/s00439-023-02560-2
Aileen A Nava 1, 2, 3, 4 , Valerie A Arboleda 1, 2, 3, 4, 5, 6
Affiliation  

The OMICs cascade describes the hierarchical flow of information through biological systems. The epigenome sits at the apex of the cascade, thereby regulating the RNA and protein expression of the human genome and governs cellular identity and function. Genes that regulate the epigenome, termed epigenes, orchestrate complex biological signaling programs that drive human development. The broad expression patterns of epigenes during human development mean that pathogenic germline mutations in epigenes can lead to clinically significant multi-system malformations, developmental delay, intellectual disabilities, and stem cell dysfunction. In this review, we refer to germline developmental disorders caused by epigene mutation as “chromatinopathies”. We curated the largest number of human chromatinopathies to date and our expanded approach more than doubled the number of established chromatinopathies to 179 disorders caused by 148 epigenes. Our study revealed that 20.6% (148/720) of epigenes cause at least one chromatinopathy. In this review, we highlight key examples in which OMICs approaches have been applied to chromatinopathy patient biospecimens to identify underlying disease pathogenesis. The rapidly evolving OMICs technologies that couple molecular biology with high-throughput sequencing or proteomics allow us to dissect out the causal mechanisms driving temporal-, cellular-, and tissue-specific expression. Using the full repertoire of data generated by the OMICs cascade to study chromatinopathies will provide invaluable insight into the developmental impact of these epigenes and point toward future precision targets for these rare disorders.



中文翻译:


组学时代:孟德尔染色质病未开发潜力的联系



OMIC 级联描述了生物系统中信息的分层流动。表观基因组位于级联的顶端,从而调节人类基因组的 RNA 和蛋白质表达,并控制细胞的身份和功能。调节表观基因组的基因(称为表观基因)协调驱动人类发育的复杂生物信号传导程序。表观基因在人类发育过程中的广泛表达模式意味着表观基因中的致病性种系突变可导致临床上显着的多系统畸形、发育迟缓、智力障碍和干细胞功能障碍。在这篇综述中,我们将表观基因突变引起的种系发育障碍称为“染色质病”。我们策划了迄今为止数量最多的人类染色质病变,并且我们的扩展方法将已确定的染色质病变的数量增加了一倍多,达到由 148 个表观基因引起的 179 种疾病。我们的研究表明,20.6% (148/720) 的表观基因导致至少一种染色质病变。在这篇综述中,我们重点介绍了 OMIC 方法应用于染色质病患者生物样本以确定潜在疾病发病机制的关键示例。快速发展的 OMIC 技术将分子生物学与高通量测序或蛋白质组学结合起来,使我们能够剖析驱动时间、细胞和组织特异性表达的因果机制。使用 OMIC 级联生成的完整数据来研究染色质病变将为了解这些表观基因的发育影响提供宝贵的见解,并为这些罕见疾病的未来精确目标指明方向。

更新日期:2023-04-29
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