Multi-omic profiling of 85 iPSC lines from familial dementia reveals cellular diversity and regulators of organoid development

Systematic molecular characterization of human induced pluripotent stem cell (iPSC) lines carrying disease-associated mutations is needed to distinguish disease-related biology from variation in cell state, genomic integrity, and genome-editing history, yet such systematic characterization is uncommon. Here, we profiled 85 human iPSC lines carrying MAPT mutations and isogenic controls using whole-genome sequencing, long-read sequencing of the MAPT locus, bulk and single-cell RNA sequencing, and DNA methylation arrays. Single-cell analyses identified four reproducible iPSC states and candidate surface markers for their isolation. Whole-genome sequencing revealed unintended editing events and recurrent 20q11.21 duplications, which were associated with increased ID1 expression and impaired cortical organoid patterning. Transcriptomic analyses identified pathways associated with organoid quality and changes linked to clonal selection and editing, underscoring the need to use unconverted lines as isogenic controls. By providing an in-depth genomic characterization of MAPT iPSCs, this dataset serves as a proof of principle to enhance iPSC utility in biological research.