June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Expression and Familial Transmission of Fuchs’ Endothelial Corneal Dystrophy (FECD) with and without TCF4 Trinucelotide Repeat (TNR) Expansion
Author Affiliations & Notes
  • Timothy T. Xu
    Alix School of Medicine, Mayo Clinic, Rochester, Minnesota, United States
  • Yi-Ju Li
    Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, United States
  • Natalie A Afshari
    Department of Ophthalmology, University of California, San Diego, San Diego, California, United States
  • Ross A. Aleff
    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States
  • Tommy A Rinkoski
    Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States
  • Sanjay V Patel
    Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States
  • Leo J Maguire
    Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States
  • Michael P Fautsch
    Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States
  • Eric Wieben
    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States
  • Keith H Baratz
    Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States
  • Footnotes
    Commercial Relationships   Timothy Xu, None; Yi-Ju Li, None; Natalie Afshari, None; Ross Aleff, None; Tommy Rinkoski, None; Sanjay Patel, None; Leo Maguire, None; Michael Fautsch, None; Eric Wieben, None; Keith Baratz, None
  • Footnotes
    Support  NEI Grant EY 25071, Mayo Clinic Career Development Award, NEI Grant EY26490
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 1187. doi:
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      Timothy T. Xu, Yi-Ju Li, Natalie A Afshari, Ross A. Aleff, Tommy A Rinkoski, Sanjay V Patel, Leo J Maguire, Michael P Fautsch, Eric Wieben, Keith H Baratz; Expression and Familial Transmission of Fuchs’ Endothelial Corneal Dystrophy (FECD) with and without TCF4 Trinucelotide Repeat (TNR) Expansion. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1187.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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