Genomics in Equine MEED: Whole-Genome Sequencing and Target Mutation Identification.

Multisystemic eosinophilic epitheliotropic disease (MEED) is a rare and severe equine disorder characterized by chronic eosinophilic inflammation, epithelial disruption, and multi-organ involvement, with an undefined genetic basis. We performed the high-depth (~40×) whole-genome sequencing of an affected horse and compared it to 40 control genomes. Over 6.3 million variants were identified, with moderate- and high-impact variants enriched in low-frequency categories, including rare and private variants absent from the controls. The affected horse was dominated by missense mutations, with relatively few high-impact variants, consistent with the distributed protein-altering effects rather than a single highly penetrant mutation. Gene prioritization and pathway analyses highlighted the disruption of cytoskeletal organization, microtubule dynamics, epithelial integrity, and immune regulation. The network analysis further revealed the interconnected structural and inflammatory pathways, suggesting a link between an impaired epithelial barrier function and immune homeostasis. Together, these findings provide the first population genomic insight into MEED and support a model in which cumulative mutations contribute to the epithelial instability and persistent inflammation characteristic of the disease.