Association and familial segregation of CTG18.1 trinucleotide repeat expansion of TCF4 gene in fuchs' endothelial corneal dystrophy

Venkateswara Mootha, Xin Gong, Hung Chih Ku, Chao Xing

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50 Citations (Scopus)

Abstract

PURPOSE. We tested the association between two intronic polymorphisms (CTG18.1 and rs613872) in TCF4 and Fuchs' endothelial corneal dystrophy (FECD), and analyzed their segregation patterns in families. METHODS. We recruited 120 unrelated Caucasian subjects with FECD and 100 controls. Available family members of probands were recruited. Genotyping of the single nucleotide polymorphism (SNP) rs613872 was performed using Sanger sequencing or real-time allelic discrimination assay. The trinucleotide repeat polymorphism, CTG18.1, was genotyped using a combination of short tandem repeat assay and triplet repeat primed PCR assay. The cytosinethymine- guanine (CTG) repeat length of ≥40 was classified as an expanded CTG18.1 allele. Association of the two loci with FECD was evaluated. Segregation in 29 families was examined. RESULTS. The two polymorphisms are in linkage disequilibrium (r2 = 0.65 in cases and 0.31 in controls). Significant associations were found between FECD and rs613872 (P = 3.1 ×10-17), expanded CTG18.1 allele (P = 6.5 ×10-25), and their haplotypes (P = 5.9 ×10-19). The odds ratio (OR) of each copy of the rs613872 G allele for FECD was estimated to be 9.5 (95% confidence interval [CI], 5.1-17.5). The OR of each copy of the CTG18.1 expanded allele was estimated to be 32.3 (95% CI, 13.4-77.6). The expanded CTG 18.1 allele cosegregated with the trait in 52% (15/29) of families with complete penetrance and 10% (3/29) with incomplete penetrance. CONCLUSIONS. We report, to our knowledge, the first independent replication of the expanded CTG 18.1 allele conferring significant risk for FECD (>30-fold increase). The expanded allele cosegregates with the trait with complete penetrance in a majority of families, but we also document cases of incomplete penetrance.

Original languageEnglish (US)
Pages (from-to)33-42
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Volume55
Issue number1
DOIs
StatePublished - Jan 2 2014

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Fuchs' Endothelial Dystrophy
Trinucleotide Repeat Expansion
Alleles
Penetrance
Guanine
Genes
Trinucleotide Repeats
Odds Ratio
Confidence Intervals
Linkage Disequilibrium
Microsatellite Repeats
Haplotypes
Single Nucleotide Polymorphism
Polymerase Chain Reaction

Keywords

  • Fuchs' dystrophy
  • Genetics
  • TCF4

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

@article{ca8fc2f1984c40cab8cd0991a537ff7c,
title = "Association and familial segregation of CTG18.1 trinucleotide repeat expansion of TCF4 gene in fuchs' endothelial corneal dystrophy",
abstract = "PURPOSE. We tested the association between two intronic polymorphisms (CTG18.1 and rs613872) in TCF4 and Fuchs' endothelial corneal dystrophy (FECD), and analyzed their segregation patterns in families. METHODS. We recruited 120 unrelated Caucasian subjects with FECD and 100 controls. Available family members of probands were recruited. Genotyping of the single nucleotide polymorphism (SNP) rs613872 was performed using Sanger sequencing or real-time allelic discrimination assay. The trinucleotide repeat polymorphism, CTG18.1, was genotyped using a combination of short tandem repeat assay and triplet repeat primed PCR assay. The cytosinethymine- guanine (CTG) repeat length of ≥40 was classified as an expanded CTG18.1 allele. Association of the two loci with FECD was evaluated. Segregation in 29 families was examined. RESULTS. The two polymorphisms are in linkage disequilibrium (r2 = 0.65 in cases and 0.31 in controls). Significant associations were found between FECD and rs613872 (P = 3.1 ×10-17), expanded CTG18.1 allele (P = 6.5 ×10-25), and their haplotypes (P = 5.9 ×10-19). The odds ratio (OR) of each copy of the rs613872 G allele for FECD was estimated to be 9.5 (95{\%} confidence interval [CI], 5.1-17.5). The OR of each copy of the CTG18.1 expanded allele was estimated to be 32.3 (95{\%} CI, 13.4-77.6). The expanded CTG 18.1 allele cosegregated with the trait in 52{\%} (15/29) of families with complete penetrance and 10{\%} (3/29) with incomplete penetrance. CONCLUSIONS. We report, to our knowledge, the first independent replication of the expanded CTG 18.1 allele conferring significant risk for FECD (>30-fold increase). The expanded allele cosegregates with the trait with complete penetrance in a majority of families, but we also document cases of incomplete penetrance.",
keywords = "Fuchs' dystrophy, Genetics, TCF4",
author = "Venkateswara Mootha and Xin Gong and Ku, {Hung Chih} and Chao Xing",
year = "2014",
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doi = "10.1167/iovs.13-12611",
language = "English (US)",
volume = "55",
pages = "33--42",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "1",

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TY - JOUR

T1 - Association and familial segregation of CTG18.1 trinucleotide repeat expansion of TCF4 gene in fuchs' endothelial corneal dystrophy

AU - Mootha, Venkateswara

AU - Gong, Xin

AU - Ku, Hung Chih

AU - Xing, Chao

PY - 2014/1/2

Y1 - 2014/1/2

N2 - PURPOSE. We tested the association between two intronic polymorphisms (CTG18.1 and rs613872) in TCF4 and Fuchs' endothelial corneal dystrophy (FECD), and analyzed their segregation patterns in families. METHODS. We recruited 120 unrelated Caucasian subjects with FECD and 100 controls. Available family members of probands were recruited. Genotyping of the single nucleotide polymorphism (SNP) rs613872 was performed using Sanger sequencing or real-time allelic discrimination assay. The trinucleotide repeat polymorphism, CTG18.1, was genotyped using a combination of short tandem repeat assay and triplet repeat primed PCR assay. The cytosinethymine- guanine (CTG) repeat length of ≥40 was classified as an expanded CTG18.1 allele. Association of the two loci with FECD was evaluated. Segregation in 29 families was examined. RESULTS. The two polymorphisms are in linkage disequilibrium (r2 = 0.65 in cases and 0.31 in controls). Significant associations were found between FECD and rs613872 (P = 3.1 ×10-17), expanded CTG18.1 allele (P = 6.5 ×10-25), and their haplotypes (P = 5.9 ×10-19). The odds ratio (OR) of each copy of the rs613872 G allele for FECD was estimated to be 9.5 (95% confidence interval [CI], 5.1-17.5). The OR of each copy of the CTG18.1 expanded allele was estimated to be 32.3 (95% CI, 13.4-77.6). The expanded CTG 18.1 allele cosegregated with the trait in 52% (15/29) of families with complete penetrance and 10% (3/29) with incomplete penetrance. CONCLUSIONS. We report, to our knowledge, the first independent replication of the expanded CTG 18.1 allele conferring significant risk for FECD (>30-fold increase). The expanded allele cosegregates with the trait with complete penetrance in a majority of families, but we also document cases of incomplete penetrance.

AB - PURPOSE. We tested the association between two intronic polymorphisms (CTG18.1 and rs613872) in TCF4 and Fuchs' endothelial corneal dystrophy (FECD), and analyzed their segregation patterns in families. METHODS. We recruited 120 unrelated Caucasian subjects with FECD and 100 controls. Available family members of probands were recruited. Genotyping of the single nucleotide polymorphism (SNP) rs613872 was performed using Sanger sequencing or real-time allelic discrimination assay. The trinucleotide repeat polymorphism, CTG18.1, was genotyped using a combination of short tandem repeat assay and triplet repeat primed PCR assay. The cytosinethymine- guanine (CTG) repeat length of ≥40 was classified as an expanded CTG18.1 allele. Association of the two loci with FECD was evaluated. Segregation in 29 families was examined. RESULTS. The two polymorphisms are in linkage disequilibrium (r2 = 0.65 in cases and 0.31 in controls). Significant associations were found between FECD and rs613872 (P = 3.1 ×10-17), expanded CTG18.1 allele (P = 6.5 ×10-25), and their haplotypes (P = 5.9 ×10-19). The odds ratio (OR) of each copy of the rs613872 G allele for FECD was estimated to be 9.5 (95% confidence interval [CI], 5.1-17.5). The OR of each copy of the CTG18.1 expanded allele was estimated to be 32.3 (95% CI, 13.4-77.6). The expanded CTG 18.1 allele cosegregated with the trait in 52% (15/29) of families with complete penetrance and 10% (3/29) with incomplete penetrance. CONCLUSIONS. We report, to our knowledge, the first independent replication of the expanded CTG 18.1 allele conferring significant risk for FECD (>30-fold increase). The expanded allele cosegregates with the trait with complete penetrance in a majority of families, but we also document cases of incomplete penetrance.

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KW - Genetics

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