Expression and Familial Transmission of Fuchs’ Endothelial Corneal Dystrophy (FECD) with and without TCF4 Trinucelotide Repeat (TNR) Expansion

Abstract

Purpose : It is unclear whether FECD demonstrates intergenerational repeat length instability observed in other repeat expansion diseases. We characterized inheritance patterns of FECD in families with (TNR+) and without (TNR-) TCF4 TNR expansion ≥ 40 repeats. TNR+ families were examined for TNR instability and disease severity in relation to TNR length.

Methods : FECD severity was graded using a modified Krachmer scale in a prospective cohort of FECD families recruited at two U.S. referral centers. DNA was extracted from leukocytes, and TCF4 TNR length was determined by using short tandem repeat assay of PCR-amplified DNA and Southern blotting of unamplified DNA. Multivariable logistic regression and multivariable generalized estimating equation models were used for statistical analysis.

Results : Among 253 members of 90 families, the apparent mode of transmission was autosomal dominant in both the 67 TNR+ and 23 TNR- families. Penetrance of the FECD phenotype in TNR+ relatives of TNR+ probands was age dependent: 38%, 63%, 94%, and 93% for age quartiles 19-46 years, 47-53 years, 54-61 years, and ≥ 62 years, respectively. The median change in TNR length from 30 TNR+ parents to 45 TNR+ offspring was 0 (interquartile range = -3 to 3), with a substantial change in repeat length in 8 cases (range = -1900 to +1900).

In a cohort of 648 unrelated subjects, including 477 FECD cases (68% female; mean age = 70 ± 10 yrs.) and 171 controls (65% female; 73 ± 11 yrs.; all ≥ 50 years), TNR expansion was found in 372 (78%) cases and 12 (7%) controls. Among TNR+ FECD cases, median TNR length of the expanded allele was 80 (range 40 - 2000), and 27 (7%) were homozygous for expansion. In the 12 TNR+ controls, median TNR length was 74 (range 43 – 103). Within the subset of TNR+ FECD patients, TNR length was associated with FECD severity after age adjustment (p = 0.02).

Conclusions : FECD families with and without TNR expansion demonstrated autosomal dominant inheritance. In contrast to other repeat-associated diseases, substantial intergenerational TNR length instability was uncommon (18%) with no clear pattern of expansion or contraction between generations. Incomplete penetrance of the phenotype was observed. As recognized previously, the majority of FECD-affected individuals in this U.S. cohort harbored TNR expansion, and disease severity was associated with repeat length.

This is a 2020 ARVO Annual Meeting abstract.