Initiation of a Multi–Center Study to Map Genes for Fuchs’ Endothelial Corneal Dystrophy

Abstract

Abstract: : Purpose:Molecular data on the genetic basis of Fuchs’ endothelial corneal dystrophy (FECD)are limited. In an effort to better characterize the disorder genetically, a multi–center study to recruit families with FECD has been initiated. Methods: Our goal is to identify 500 families with FECD using the consortium model. Advanced FECD cases will be identified and the extent of familial clustering using a clinical measure of severity as a semi–quantitative trait will be determined. Family history, clinical, and other demographic information will be collected using a standardized instrument. Histopathologic confirmation of advanced index cases will be obtained. Blood samples will be collected for molecular genetic analyses. Results: Clinical information and blood samples on a total of 45 sib pairs, 3 grandparent–grandchild pairs, and 4 avuncular pairs in 24 families from three pilot sites have been obtained. A quantitative trait grading system of the degree of clinical FECD is being employed ranging from 0–6: grades 0 or 1 (unaffected), grades 4–6 (affected), all other grades (intermediate). Of the 24 FECD probands, 2 were African American (2 female; mean age = 77.5 yrs), 19 were Caucasian (13 female, mean age = 65.1yrs; 6 male, mean age = 58.8 yrs), 1 was Hispanic (female; age = 72 yrs) and 2 were other (female; mean age = 60 yrs). The severity grades ranged from 5 to 6 among the probands in the worse eye. Thirty sibs of the probands (9 males, 21 females; mean age 64.7 years) were also recruited with an average clinical severity grade of 2.6. Of the individuals who are considered as affected, 10 are biopsy confirmed. To assess interobserver variability, thirty participants (right and left eyes; N=60) had the FECD clinical severity grade determined independently by two trained observers. The correlation coefficient for grade assigned by each observer for the left and right eyes was > 98%. The weighted kappa statistic was 0.93 (95% Confidence Interval = 0.87–0.99) for the right eye, and 0.94 (95% Confidence Interval = 0.88–1.00) for the left eye. This suggests that our grading scheme can be utilized effectively across the entire multi–center study. Conclusions: Our data indicate that although there is significant familial clustering of disease, the range of severity may vary, suggesting that FECD is a complex disease that would be amenable to genome–wide analyses in a larger cohort.

Keywords: cornea: endothelium • genetics