Tissue-level heterogeneity in FECD: Descemet's membrane phenotypes and association with TCF4 CTG18.1 expansion†.

Late-onset Fuchs endothelial corneal dystrophy (FECD) is commonly framed as a corneal endothelial disease characterised by guttae accumulation and progressive thickening of Descemet's membrane (DM). However, clinical forms and evolutionary profiles vary widely. Vaitinadapoulé et al systematically analysed as many as 500 keratoplasty-derived DMs from 25 European centres using flat mounts and transmitted light microscopy with structured scoring of extracellular matrix (ECM) lesions. The study revealed five FECD phenotypes and spatially organised lesion patterns and supports multiple pathological phenotypes. Radial organisation emerged as a dominant architectural theme, often accompanied by peripheral striae, with changes evident in both central and peripheral DM. Principal component analysis and unsupervised clustering showed modest separability, while manual classification identified dominant phenotypes with appreciable overlap, suggesting pathological phenotypes arise from a combination of lesion features and organisational patterns. In a genotyped subset, DM architectures differed by TCF4 CTG18.1 expansion status, linking tissue architecture to repeat biology. This ECM atlas provides a pathology-anchored framework for FECD heterogeneity and motivates prospective clinical correlation and quantitative image analysis. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.