PDF(Pubmed)
Abstract：
Pathogenic variants in KANSL1 and 17q21.31 microdeletions are causative of Koolen-de Vries syndrome (KdVS), a neurodevelopmental syndrome with characteristic facial dysmorphia. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes have identifiable patterns of DNA methylation (DNAm) change: DNAm signatures or episignatures. Given the role of KANSL1 in histone acetylation, we tested whether variants underlying KdVS are associated with a DNAm signature. We profiled whole-blood DNAm for 13 individuals with KANSL1 variants, four individuals with 17q21.31 microdeletions, and 21 typically developing individuals, using Illumina\'s Infinium EPIC array. In this study, we identified a robust DNAm signature of 456 significant CpG sites in 8 individuals with KdVS, a pattern independently validated in an additional 7 individuals with KdVS. We also demonstrate the diagnostic utility of the signature and classify two KANSL1 VUS as well as four variants in individuals with atypical clinical presentation. Lastly, we investigated tissue-specific DNAm changes in fibroblast cells from individuals with KdVS. Collectively, our findings contribute to the understanding of the epigenetic landscape related to KdVS and aid in the diagnosis and classification of variants in this structurally complex genomic region.
摘要：
KANSL1和17q21.31微缺失的致病变异是Koolen-deVries综合征（KdVS）的病因，具有特征性面部畸形的神经发育综合征。我们先前的工作表明，由表观遗传调节基因中的致病变异引起的综合征具有可识别的DNA甲基化（DNAm）变化模式：DNAm标记或表观标记。鉴于KANSL1在组蛋白乙酰化中的作用，我们测试了KdVS基础的变体是否与DNAm签名相关.我们对13名具有KANSL1变体的个体的全血DNAm进行了分析，四个人17q21.31微缺失，和21个典型的发育中的个体，使用Illumina的InfiniumEPIC数组。在这项研究中,我们在8名KdVS患者中鉴定出了456个重要CpG位点的稳健DNAm特征，该模式在另外7名KdVS患者中独立验证。我们还证明了该特征的诊断实用性，并对具有非典型临床表现的个体中的两个KANSL1VUS以及四个变体进行了分类。最后,我们研究了KdVS患者成纤维细胞中组织特异性DNAm的变化.总的来说，我们的发现有助于理解与KdVS相关的表观遗传景观,并有助于这一结构复杂的基因组区域的变异诊断和分类.
