Molecular dissection of germline chromothripsis in a developmental context

Complex germline genomic rearrangements can affect many genes and regulatory elements, but the precise mechanisms that caused the phenotype of patients with such rearrangements are often unknown. To dissect the impact of germline chromothripsis in a relevant developmental context, we performed trio-based RNA expression analysis on blood cells,induced pluripotent stem (iPS) cells and iPS-cell derived neuronal cells from a patient with de novo germline chromothripsis and both healthy parents. In addition, we performed Hi-C on iPS cell-derived neural progenitors of the patient and the father to study the effects of the chromothripsis rearrangements on the architecture of the derivative
chromosomes. We demonstrate that a combination of patient-derived iPS cell differentiation and trio-based molecular profiling is a powerful approach to improve the interpretation of pathogenic complex genomic rearrangements.EGA study EGAS00001001896

生殖系复杂基因组重排可累及众多基因及调控元件，但此类重排引发患者表型的确切分子机制迄今仍多未明。为解析生殖系染色体碎裂（chromothripsis）在相关发育场景中的功能影响，我们针对1例新发生殖系染色体碎裂患者及其两名健康双亲的血液细胞、诱导多能干细胞（induced pluripotent stem cells，iPS细胞）以及iPS细胞诱导分化的神经元细胞，开展了基于三人家系的RNA表达谱分析。此外，我们分别对患者与父亲的iPS细胞来源神经前体细胞开展Hi-C分析，以探究染色体碎裂重排对衍生染色体三维结构的调控作用。本研究证实，将患者来源iPS细胞分化模型与三人家系分子谱分析相结合，可有效优化致病性复杂基因组重排的解读精度与可靠性。EGA study EGAS00001001896