Abstract：
Emerging research has demonstrated that genomic alterations disrupting topologically associated domains (TADs) and chromatin interactions underlie the pathogenic mechanisms of specific copy number variants (CNVs) in neurodevelopmental disorders. We report two patients with a de novo deletion and a duplication in chromosome 4q31, potentially causing FBX-related neurodevelopmental syndrome by affecting the regulatory region of FBXW7. High-throughput chromosome conformation capture (Hi-C) analysis using available capture data in neural progenitor cells revealed the rewiring of the TAD boundary close to FBXW7. Both patients exhibited facial dysmorphisms, cardiac and limb abnormalities, and neurodevelopmental delays, showing significant clinical overlap with previously reported FBXW7-related features. We also included an additional 10 patients with CNVs in the 4q31 region from the literature and the DECIPHER database for Hi-C analysis, which confirmed that disruption of the regulatory region of FBXW7 likely contributes to the developmental defects observed in these patients.
摘要：
新兴研究表明，破坏拓扑相关域（TAD）和染色质相互作用的基因组改变是神经发育障碍中特定拷贝数变体（CNV）的致病机制的基础。我们报告了两名在4q31号染色体上有从头缺失和重复的患者，可能通过影响FBXW7的调节区而导致FBX相关的神经发育综合征。使用神经祖细胞中可用的捕获数据进行的高通量染色体构象捕获（Hi-C）分析揭示了TAD边界在FBXW7附近的重新布线。两名患者均表现出面部畸形，心脏和肢体异常，和神经发育迟缓，显示与先前报道的FBXW7相关特征的显著临床重叠。我们还纳入了另外10名来自文献和DECIPHER数据库的4q31区域CNV患者，用于Hi-C分析，这证实了FBXW7调控区的破坏可能导致这些患者的发育缺陷。
