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Keith Baratz, Ross Aleff, Yi-Ju Li, Malinda Butz, Simon Gregory, Gordon Klintworth, W. Edward Highsmith, Natalie Afshari, Eric Wieben; A Family-based Investigation of the Role of TCF4 Trinucleotide Repeat Expansion in Fuchs Endothelial Corneal Dystrophy (FECD). Invest. Ophthalmol. Vis. Sci. 2013;54(15):4560.
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© ARVO (1962-2015); The Authors (2016-present)
Previous studies of unrelated FECD subjects and unaffected controls revealed a strong association between the presence of more than 50 repeats of the trinucleotide TGC in the third intron of the transcription factor 4 (TCF4) gene and the incidence of FECD. To evaluate the role of this triplet repeat in the inheritance of the disease, we examined whether this trinucleotide repeat expansion in TCF4 segregates with the incidence of FECD in families.
The corneas of FECD probands and their family members were graded by using a modified Krachmer scale (grade 0 - 6). Leukocyte-derived DNA was evaluated by fluorescence based short tandem repeat (STR) assays to calculate the TGC repeat length of both alleles in all affected and unaffected participants. Southern blot analysis was used to interrogate the repeat status in all DNA samples that had only a single allele by STR analysis. A total of 30 participants (33-91 years) from 11 families were included.
The size of the trinucleotide repeat in patients with FECD ranged between 12 and 89 TGC repeats. Expansion above 50 repeats tracked with the disease in six of eleven families. In one additional family, 2 of 4 participants had FECD and repeat expansions of 59 and 62 TGC repeats, one member (48 yrs.) had equivocal disease with expansion (grade 1; 59 repeats), while the fourth family member (53 yrs.) had TGC expansion but no evidence of disease (gr. 0; 59 repeats). In the remaining four families, no repeat expansions above the 50 repeat threshold for disease association were identified in any of the seven affected (≥ gr. 2) and one equivocally affected (gr. 1) family members. Among families with expanded TGC repeats, the variation in repeat size was between 0 and 3 repeats in parent-child transmission and between 0 and 6 repeats between siblings.
Moderate expansions of the TGC repeat in TCF4 predicted FECD status in 6 of 11 FECD families. In a subset of FECD families, there was no expansion of this trinucleotide repeat. Thus, the repeat status may be useful and necessary in stratifying patients in further genetic studies of FECD and in studies of disease pathophysiology using FECD-affected tissue. In this small cohort, the expansion size varied minimally within families.
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