不断扩大范围的遗传综合征的特征在于DNA甲基化谱的全基因组破坏,称为表观标记。签名是不同的,高度敏感,以及最近应用于遗传综合征临床诊断的特异性生物标志物。表观标记包含在更广泛的疾病特异性基因组DNA甲基化变化中,它们可以在不同的条件之间共享显著的重叠。在这项研究中,我们进行了功能基因组评估,并比较了与65个遗传综合征相关的疾病特异性和重叠的全基因组DNA甲基化变化和之前描述的表观特征.我们证明了疾病特异性和反复发生的全基因组差异甲基化探针(DMPs)和区域(DMRs)的证据。分析的大多数神经发育遗传综合征的DMP和DMRs的总体分布显示基因启动子和CpG岛的大量富集,以及更多可变的基因间区域的代表性不足。分析显示DMPs和DMRs在与神经发育相关的基因通路和过程中显著富集,包括神经发生,突触信号和突触传递。这项研究通过证明突变基因的功能与随后的基因组DNA甲基化谱之间的相关性,作为遗传性神经发育障碍分子病因的关键功能元件,扩展了DNA甲基化表观标记的诊断实用性。
An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as
episignatures.
Episignatures are distinct, highly sensitive, and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes.
Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes, which can share significant overlap among different conditions. In this study, we performed functional genomic assessment and comparison of disorder-specific and overlapping genome-wide DNA methylation changes related to 65 genetic syndromes with previously described
episignatures. We demonstrate evidence of disorder-specific and recurring genome-wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under-representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation
episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders.