Fuchs Endothelial Corneal Dystrophy (FECD) is a sex-linked, bilaterally-symmetric, slowly-progressing degeneration of the corneal endothelium. This debilitating disorder becomes symptomatic in the fifth or sixth decade of life, and affects 2-4x more women than men. The clinical presentation of FECD varies, but often includes corneal edema that results in a loss of corneal clarity, painful episodes of recurrent corneal erosions, impaired visual acuity. In some cases the disease may result in blindness. Most patients ultimately require corneal transplantation; thus, FECD is a leading indication of corneal transplantation in developed countries. The pathophysiology underlying FECD remains unknown, with a genetic predisposition being reported as the most significant risk factor for disease.
The Fuchs Genetics Consortium began in May, 2010, with discussions between NEI staff and three founding groups from Case Western Reserve University, Duke University, and Johns Hopkins University. A multi-center consortium, with defined governance structure, was established with the goal of determining the genetic architecture of FECD. The consortium group has assembled a large patient cohort that is uniformly graded for disease severity, using slit lamp microscopy and the Krachmer grading scale. Data dictionaries for case-control status and informative covariates were compared and adjudicated.
The consortium conducted a genome-wide association study (GWAS) at the Center for Inherited Disease Research, using 1425 cases and 2525 controls. Initial analysis of this GWAS data will be followed by replication studies using next-generation sequencing to saturate the genomes/exomes of patients for pathogenetic variations. This information will inform investigations into genetic causality and specific disease pathophysiology, as well as research into the function of these gene products in the normal state. Given the dearth of biological data on corneal proteins, the growing need for engineered replacement tissue, and the significant resources to be garnered by this group, there will be unique opportunities to advance the field. Major outstanding questions include, 1) why do some individuals have severe problems, requiring transplant surgery, while others have milder phenotypic manifestations; 2) what is the extent of heterogeneity for FECD; and 3) what is the functional importance of these novel genes, particularly their role in normal ocular development. Reducing FECD incidence could lessen the need for surgical intervention, thus decreasing medical care and costs, and improve clinical outcomes.
Supported by grants R01 EY016482 (Iyengar), R01 EY016514 (Klintworth), and R01 EY016835 (Gottsch and Katsanis).