Lee Sophia N, Banda Erin C, Qiao Lu, Thompson Sarah L, Singh Karan, Hagenson Ryan A, Davoli Teresa, Pinter Stefan F, Sheltzer Jason M
Yale University School of Medicine, New Haven, CT, USA.
Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, USA.
bioRxiv. 2025 Aug 22:2024.11.17.624023. doi: 10.1101/2024.11.17.624023.
Chromosomal rearrangements on the short arm of Chromosome 8 cause 8p syndrome, a rare developmental disorder characterized by neurodevelopmental delays, epilepsy, and cardiac abnormalities. While significant progress has been made in managing the symptoms of 8p syndrome and other conditions caused by large-scale chromosomal aneuploidies, no therapeutic approach has yet been demonstrated to target the underlying disease-causing chromosome. Here, we establish a two-step approach to eliminate the abnormal copy of Chromosome 8 and restore euploidy in cells derived from an individual with a complex rearrangement of Chromosome 8p. Transcriptomic analysis revealed 361 differentially expressed genes between the proband and the euploid revertant, highlighting genes both within and outside the 8p region that may contribute to 8p syndrome pathology. Furthermore, we demonstrate that the proband exhibits a significant defect in neural differentiation that could be partially rescued by treatment with small-molecule inhibitors of cell death. Our work demonstrates the feasibility of using chromosome engineering to correct complex aneuploidies in vitro and establishes a platform to further dissect the pathophysiology of 8p syndrome and other conditions caused by chromosomal rearrangements.
8号染色体短臂上的染色体重排导致8p综合征，这是一种罕见的发育障碍，其特征为神经发育迟缓、癫痫和心脏异常。虽然在管理8p综合征及其他由大规模染色体非整倍性引起的病症的症状方面已取得显著进展，但尚未证明有针对潜在致病染色体的治疗方法。在此，我们建立了一种两步法，以消除8号染色体的异常拷贝并在源自具有复杂8p染色体重排个体的细胞中恢复整倍性。转录组分析揭示了先证者与整倍体回复体之间361个差异表达基因，突出了8p区域内外可能导致8p综合征病理的基因。此外，我们证明先证者在神经分化方面存在显著缺陷，用细胞死亡小分子抑制剂治疗可部分挽救该缺陷。我们的工作证明了使用染色体工程在体外纠正复杂非整倍性的可行性，并建立了一个平台以进一步剖析8p综合征及其他由染色体重排引起的病症的病理生理学。
