Wallman Daniel J, Homma Sachiko T, Finton Madeleine, Beermann MaryLou, Jacob Anjali, Choksi Semil P, Pletcher Steven D, Xu Huihui, Bawa Pushpinder Singh, Reiter Jeremy F, Horani Amjad, Brody Steven L, Berical Andrew, Hawkins Finn J
Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA.
The Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA.
bioRxiv. 2025 Jul 31:2025.07.28.667211. doi: 10.1101/2025.07.28.667211.
Advances in genetic and transcriptomic technologies have identified large numbers of genes and variants of potential importance to human disease. Determining the function of these genes and variants is a critical bottleneck in understanding disease etiology. Variants of uncertain significance (VUS) are highly prevalent in our genomes, but our ability to identify them significantly outpaces our ability to determine their molecular and clinical consequences. We developed a genetically tractable induced pluripotent stem cell (iPSC) based platform to investigate gene variant pathogenicity in lung disease, using primary ciliary dyskinesia (PCD) as a model. We identified an individual with a clinical diagnosis of PCD and a VUS in the gene . Through gene-editing of iPSC-derived airway basal stem cells (iBCs), we precisely defined the molecular and cellular pathogenicity of the variant providing a successful application of the iPSC system to diagnose a lung disease.
基因和转录组技术的进步已经鉴定出大量对人类疾病具有潜在重要性的基因和变异体。确定这些基因和变异体的功能是理解疾病病因的关键瓶颈。意义未明的变异体（VUS）在我们的基因组中高度普遍，但我们识别它们的能力明显超过了确定其分子和临床后果的能力。我们开发了一个基于基因易处理的诱导多能干细胞（iPSC）的平台，以原发性纤毛运动障碍（PCD）为模型，研究肺部疾病中基因变异体的致病性。我们鉴定出一名临床诊断为PCD且该基因存在VUS的个体。通过对iPSC衍生的气道基底干细胞（iBCs）进行基因编辑，我们精确地定义了该变异体的分子和细胞致病性，成功地将iPSC系统应用于肺部疾病的诊断。
