Image-based, pooled phenotyping reveals multidimensional, disease-specific variant effects.

ABSTRACT: Genetic variants often produce complex phenotypic effects that confound current assays and predictive models. We developed Variant in situ sequencing (VIS-seq), a pooled, image-based method that measures 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 that captured variant-driven changes in protein abundance, localization, activity and cell architecture. We identified gain-of-function LMNA variants that reshape the nucleus and autism-associated PTEN variants that mislocalize. Morphological profiles predicted variant pathogenicity with near-perfect accuracy and distinguished autism-linked from tumor syndrome-linked PTEN variants. Mo

SUBMITTER: Pendyala S 

PROVIDER: S-EPMC12236469 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature