Image-based, pooled phenotyping reveals multidimensional, disease-specific variant effects
- Author(s)
- Pendyala, S; Partington, K; Bradley, N; McEwen, AE; Straub, G; Kim, HJ; Fayer, S; Holmes, DL; Sitko, KA; Garge, RK; Wang, ZR; Wheelock, MK; Vandi, AJ; Powell, RL; Friedman, CE; McDermot, E; Kishore, N; Roth, FP; Rubin, AF; Yang, KC; Starita, LM; Noble, WS; Fowler, DM;
- Journal Title
- Cell
- Publication Type
- May 12
- Abstract
- Genetic variants produce complex phenotypic effects that confound current assays and predictive models. We developed variant in situ sequencing (VIS-seq), a pooled, image-based method measuring variant effects on molecular and cellular phenotypes in diverse cell types. Applying VIS-seq to ∼3,000 LMNA and PTEN variants yielded high-dimensional morphological profiles capturing changes in protein abundance, localization, activity, and cell architecture. VIS-seq identified a subset of linker-subdomain LMNA variants that increase nuclear circularity, in contrast to aggregating or low-abundance rod-subdomain variants that decrease circularity. VIS-seq also identified autism-associated PTEN variants that mislocalize and accurately distinguished autism-linked from tumor syndrome-linked and gnomAD control variants. Most variants impacted a multidimensional phenotypic continuum not recapitulated by any single functional readout. By linking variants to cell images at scale, VIS-seq illuminates how variant effects cascade from molecules to subcellular structures to cells, providing a framework for resolving the complexity of variant function.
- Publisher
- Cell Press
- Keywords
- functional genomics; genetic variation; multiplexed assays of variant effect; optical pooled screening; pleiotropy
- Research Division(s)
- Bioinformatics and Computational Biology
- PubMed ID
- 42127894
- Publisher's Version
- https://doi.org/10.1016/j.cell.2026.04.031
- Open Access at Publisher's Site
https://doi.org/10.1016/j.cell.2026.04.031- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-05-25 11:04:08
Last Modified: 2026-05-25 11:04:18