Atlas of CRISPR Correction of Pathogenic Human Genetic Variants

Inherited genetic disorders impact at least 300 million individuals worldwide, presenting a significant therapeutic challenge. Although CRISPR-based genome editing offers a promising avenue for targeted interventions, the pathogenic and likely pathogenic variants amenable to such treatments have yet to be fully delineated. Here, we present the mEdit platform (https://igimedit.org) alongside a library of 179,819 pathogenic and likely pathogenic germline variants across 4,659 genes that include their potential correctability using CRISPR-based approaches. mEdit assesses the therapeutic editability of these variants by reporting mutation-specific guide RNAs (gRNA), efficiency scoring, off-target evaluation, and variant annotations from different databases. Our analysis reveals that >95% of these variants are targetable by at least one CRISPR tool, including >14% suitable for base editing strategies. Furthermore, we introduce the concept of histoetiology to assign the root-cause tissues of these variants, providing crucial insights into their clinical editing tractability. This study establishes a strategic roadmap for prioritizing CRISPR-based therapeutic development, highlighting the opportunities and gaps in the current landscape of gene-editable human mutations. Our findings underscore the potential of CRISPR technologies to address a vast array of genetic disorders, paving the way for future advances in genetic medicine. In particular, given the established clinical tractability of gene editing in the eye, the hematopoietic system, and the liver, our analysis nominates, for the first time, ~25% of the human mutome as directly amenable to in-the-clinic CRISPR gene editing therapeutic development.