PDF(Pubmed)
Abstract：
NF1 microdeletion syndrome, accounting for 5-11% of NF1 patients, is caused by a deletion in the NF1 region and it is generally characterized by a severe phenotype. Although 70% of NF1 microdeletion patients presents the same 1.4 Mb type-I deletion, some patients may show additional clinical features. Therefore, the contribution of several pathogenic mechanisms, besides haploinsufficiency of some genes within the deletion interval, is expected and needs to be defined. We investigated an altered expression of deletion flanking genes by qPCR in patients with type-1 NF1 deletion, compared to healthy donors, possibly contributing to the clinical traits of NF1 microdeletion syndrome. In addition, the 1.4-Mb deletion leads to changes in the 3D chromatin structure in the 17q11.2 region. Specifically, this deletion alters DNA-DNA interactions in the regions flanking the breakpoints, as demonstrated by our 4C-seq analysis. This alteration likely causes position effect on the expression of deletion flanking genes.Interestingly, 4C-seq analysis revealed that in microdeletion patients, an interaction was established between the RHOT1 promoter and the SLC6A4 gene, which showed increased expression. We performed NGS on putative modifier genes, and identified two \"likely pathogenic\" rare variants in RAS pathway, possibly contributing to incidental phenotypic features.This study provides new insights into understanding the pathogenesis of NF1 microdeletion syndrome and suggests a novel pathomechanism that contributes to the expression phenotype in addition to haploinsufficiency of genes located within the deletion.This is a pivotal approach that can be applied to unravel microdeletion syndromes, improving precision medicine, prognosis and patients\' follow-up.
摘要：
NF1微缺失综合征，占NF1患者的5-11%，由NF1区域中的缺失引起,并且其通常以严重表型为特征。虽然70%的NF1微缺失患者表现出相同的1.4MbI型缺失，一些患者可能表现出额外的临床特征。因此,几种致病机制的贡献，除了缺失区间内某些基因的单倍体不足，是预期的，需要定义。我们通过qPCR研究了1型NF1缺失患者中缺失侧翼基因的表达改变，与健康的捐赠者相比，可能有助于NF1微缺失综合征的临床特征。此外,1.4Mb缺失导致17q11.2区域的3D染色质结构发生变化。具体来说,这种缺失改变了断点侧翼区域的DNA-DNA相互作用，正如我们的4C-seq分析所证明的那样。这种改变可能导致对缺失侧翼基因表达的位置效应。有趣的是,4C-seq分析显示，在微缺失患者中，在RHOT1启动子和SLC6A4基因之间建立了相互作用，显示表达增加。我们对推定的修饰基因进行了NGS，并确定了RAS途径中的两种“可能致病”罕见变异，可能有助于偶然的表型特征。这项研究为理解NF1微缺失综合征的发病机理提供了新的见解，并提出了一种新的病理机制，除了位于缺失内的基因的单倍体不足外，还有助于表达表型。这是一种关键的方法，可以应用于解开微缺失综合征，改善精准医学，预后和患者随访。
