Prevalence of Transcription Factor 4 Gene Triplet Repeat Expansion Associated with Fuchs' Endothelial Corneal Dystrophy in the United States and Global Populations.

Objective: An intronic cytosine-thymine-guanine (CTG) triplet repeat expansion in the transcription factor 4 gene () gene (CTG18.1) confers significant risk for the development of Fuchs' endothelial corneal dystrophy (FECD). The objective of this study was to conduct an unbiased survey of the CTG18.1 repeat expansion allele frequencies in a multiethnic population-based cohort from the United States and in global populations.

Design: Cross-sectional study.

Subjects: Dallas Heart Study (DHS) cohort including 1599 African Americans (AAs), 1028 European Americans (EAs), and 458 Latinos; 2500 individuals from the 1000 Genomes Project (1KGP) sampled from 26 populations across 5 continents.

Methods: We genotyped the CTG18.1 short tandem repeat (STR) in DHS using targeted polymerase chain reaction amplification followed by fragment analysis. We also inferred the CTG18.1 repeat genotype based on short-read whole-genome sequencing in 1KGP using the computational tool ExpansionHunter.

Main Outcome Measures: The prevalence of an expanded CTG18.1 allele with 40 repeats was determined in United States and global populations.

Results: The carrier rates of the expanded allele were 3.1%, 8.1%, and 3.3% in AAs, EAs, and Latinos, respectively, in the DHS, and 2.7%, 9.5%, 5.2%, 7.2%, and 5.2% in the African (AFR), European (EUR), East Asian, South Asian, and admixed American continental populations, respectively, in the 1KGP. The distributions of the CTG18.1 repeat in DHS and in 1KGP are similar. The median repeat length was ∼17 with the interquartile range between 12 and 23 in the DHS populations. The median repeat length was ∼19 in all the 1KGP populations with the interquartile range between 13 and 26. The highest prevalence of the expanded allele carriers ranging from 12.1% to 12.5% was observed in some EUR and admixed American subpopulations. The frequency of expanded alleles carriers was absent or low (0%-1.9%) in subpopulations of West Africa but was present at 6.2% in a Kenyan subpopulation in East Africa.

Conclusions: The repeat expansion is most prevalent in people of EUR ancestry and least in AFR ancestry, which is consistent with FECD prevalence. The expanded CTG18.1 allele is the most common disease-causing STR in humans with worldwide implications for corneal disease.

Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.