Genetics of Fuchs corneal endothelial dystrophy – An update
Authors: Mascarelli Frederic 
Published: December 2022

Fuchs endothelial corneal dystrophy (FECD) is the most common primary corneal endothelial dystrophy. It is a progressive, bilateral eye disease that may lead to blindness. There is no primary prevention for FECD. Corneal transplantation remains the only definitive treatment. FECD is a complex and heterogeneous genetic disease with interaction between genetic and environmental factors, including gender, smoking and exposure to ultraviolet light. The most recent IC3D classification categorizes FECD into 2 forms: an extremely rare early‐onset and a late‐onset form.

The early onset FECD is associated with autosomal dominant mutations in the gene encoding the alpha 2 subunit of collagen 8, an important structural component of the Descemet membrane (DM). Most of the cases present in the third decade with an equal distribution between men and women. When observed by light and electron microscopy, three forms are described: pure corneal guttae; DM of unusual thickness but without guttae; and guttae buried by subsequent layers of more posterior extracellular matrix.

Patients with late‐onset FECD typically manifest changes by the fifth decade of life. The first defining clinical sign is the presence of guttae. As individuals age, the cornea develops more and more guttae and increases in thickness, causing glare, halos, and reduced visual acuity. With more advanced disease, stromal edema ensues along with subepithelial fibrosis. When assessed with specular microscopy, the prevalence of guttae is higher in white (11.2%) than East Asian (5.5%) populations, and higher in females (5.5%–11%) than males (1.5%–7%).

Although the median age of onset for the late‐onset FECD is at least four decades later than that of the early onset form, both display a similar linear rate of disease progression. It is not clear which comes first, abnormal corneal endothelial cells (CECs) with a defective synthetic/secretory capacity producing guttae and thickening the DM, or remodelling of the DM through synthesis, degradation, reassembly and chemical modification, resulting in CEC apoptosis.

The genetics of the late‐onset FECD is complex and multifactorial with variable expressivity and incomplete penetrance. The late‐onset FECD is sporadic with no family history or autosomal dominant.

An overview of our current understanding of the genetics of the late‐onset FECD will be provided, with a description of the different genetic variants that segregate with the disease, including variants in TCF8, AGBL1, LOXHD1 and SLC4A11 gene. The mutations in these genes collectively account for only a small proportion of total FECD. Thus, the presentation will focus on variations in the transcription factor 4 (TCF4) gene on chromosome 18q21.1, which are the most significant genetic risk factors associated with FECD. Further, the potential molecular effects of the intronic CTG trinucleotide repeat (CTG18.1) expansion in TCF4 will be described. Finally, talk will debate the hypothesis that specific genetic subtypes of FECD harbour a unique mechanism of dysregulation in addition to sharing converging common downstream features, given that all FECD cases with or without gene mutations experience the same phenotypic endpoint: presence of guttae and loss of CECs.