Oriol Busquets, Hanqin Li, Khaja Mohieddin Syed, Pilar Álvarez Jerez, Jesse Dunnack, Riana Lo Bu, Yogendra Verma, Gabriella Pangilinan, Annika Martin, Jannes Straub, YuXin Du, V Simon, Steven Poser, Zipporiah Bush, Jessica Diaz, Atehsa Sahagun, Jianpu Gao, Samantha Hong, Dena Hernández, Kristin Levine, Nathalie Pochet, Ezgi O. Booth, Marco Blanchette, Helen S. Bateup, Donald C. Rio, Cornelis Blauwendraat, Dirk Hockemeyer, Frank Soldner
Abstract Genome-edited human pluripotent stem cells (hPSCs) provide a powerful platform to study complex diseases such as Parkinson’s disease (PD). Here, we describe iSCORE-PD, an isogenic collection of 65 genome-edited hPSC lines carrying disease-causing or high-risk variants in 11 PD-linked genes ( SNCA, PRKN, PINK1, DJ1/PARK7, LRRK2, ATP13A2, FBXO7, DNAJC6, SYNJ1, VPS13C , and GBA1 ). All lines are derived from a well-characterized female hESC line and subjected to extensive quality control. Whole-genome sequencing reveals that genetic variation between lines, largely confined to non-coding regions, is minimal relative to inter-individual differences in patient-derived hiPSCs, with most variation arising from random mutations acquired during cell culture rather than genome-editing-induced off-target effects. Including multiple independently derived clones per mutation can control for this random genetic drift. Our systematic approach ensures high quality of this publicly available iSCORE-PD resource, highlights the advantages of prime editing over conventional CRISPR/Cas9 methods, and establishes best practices for generating disease-modeling hPSC collections.