Expansion of CTG18.1 trinucleotide repeat in TCF4 is a potent driver of fuchs’ corneal dystrophy

Shivakumar Vasanth, Allen Eghrari, Briana C. Gapsis, Jiangxia Wang, Nicolas F. Haller, Walter J. Stark, Nicholas Katsanis, Sheikh Amer Riazuddin, John D Gottsch

Research output: Contribution to journalArticle

Abstract

PURPOSE. To analyze the expansion of CTG18.1 allele associated with Fuchs’ corneal dystrophy (FCD) in our large cohort of late-onset FCD cases. METHODS. CTG repeats within the CTG18.1 allele were estimated by short tandem repeat (STR) and triplet primed PCR (TP-PCR) assays in our large cohort of 574 late-onset FCD cases and 354 controls and large multigeneration familial cases. The age versus severity relationships were analyzed in FCD genotypes, namely, nonexpanded (N/N), monoallelic expansion (N/X), and biallelic expansion (X/X) with N ≤ 40 CTG monomers. The threshold for causality conferred by an expansion of CTG18.1 was identified by excluding the population of FCD cases who harbored an allele length equivalent to the maximum CTG monomers observed in the controls. RESULTS. The expanded CTG18.1 for (CTG)n>40showed a strong association (P= 1.56 X 10-82) with FCD. Importantly, we delineated the threshold of expansion to 103 CTG repeats above which the allele confers causality in 17.8% of FCD cases. Regression analyses demonstrated a significant correlation between disease severity and age in individuals who harbor either a monoallelic expansion or a biallelic expansion at (CTG)n>40. These analyses helped predict FCD in two previously unaffected individuals based on their CTG18.1 expansion genotype. CONCLUSIONS. A monoallelic expansion of CTG18.1 contributes to increased disease severity and is causal at (CTG)n>103, whereas a biallelic expansion is sufficient to be causal for FCD at (CTG)n>40. This study highlights the largest contributory causal allele for FCD.

Original languageEnglish (US)
Pages (from-to)4531-4536
Number of pages6
JournalInvestigative Ophthalmology and Visual Science
Volume56
Issue number8
DOIs
StatePublished - 2015

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Fuchs' Endothelial Dystrophy
Trinucleotide Repeat Expansion
Alleles
Causality
Genotype
Microsatellite Repeats

Keywords

  • Corneal endothelium
  • CTG18.1
  • Fuchs’ corneal dystrophy
  • Repeat expansion
  • TCF4

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Expansion of CTG18.1 trinucleotide repeat in TCF4 is a potent driver of fuchs’ corneal dystrophy. / Vasanth, Shivakumar; Eghrari, Allen; Gapsis, Briana C.; Wang, Jiangxia; Haller, Nicolas F.; Stark, Walter J.; Katsanis, Nicholas; Riazuddin, Sheikh Amer; Gottsch, John D.

In: Investigative Ophthalmology and Visual Science, Vol. 56, No. 8, 2015, p. 4531-4536.

Research output: Contribution to journalArticle

Vasanth, Shivakumar ; Eghrari, Allen ; Gapsis, Briana C. ; Wang, Jiangxia ; Haller, Nicolas F. ; Stark, Walter J. ; Katsanis, Nicholas ; Riazuddin, Sheikh Amer ; Gottsch, John D. / Expansion of CTG18.1 trinucleotide repeat in TCF4 is a potent driver of fuchs’ corneal dystrophy. In: Investigative Ophthalmology and Visual Science. 2015 ; Vol. 56, No. 8. pp. 4531-4536.
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abstract = "PURPOSE. To analyze the expansion of CTG18.1 allele associated with Fuchs’ corneal dystrophy (FCD) in our large cohort of late-onset FCD cases. METHODS. CTG repeats within the CTG18.1 allele were estimated by short tandem repeat (STR) and triplet primed PCR (TP-PCR) assays in our large cohort of 574 late-onset FCD cases and 354 controls and large multigeneration familial cases. The age versus severity relationships were analyzed in FCD genotypes, namely, nonexpanded (N/N), monoallelic expansion (N/X), and biallelic expansion (X/X) with N ≤ 40 CTG monomers. The threshold for causality conferred by an expansion of CTG18.1 was identified by excluding the population of FCD cases who harbored an allele length equivalent to the maximum CTG monomers observed in the controls. RESULTS. The expanded CTG18.1 for (CTG)n>40showed a strong association (P= 1.56 X 10-82) with FCD. Importantly, we delineated the threshold of expansion to 103 CTG repeats above which the allele confers causality in 17.8{\%} of FCD cases. Regression analyses demonstrated a significant correlation between disease severity and age in individuals who harbor either a monoallelic expansion or a biallelic expansion at (CTG)n>40. These analyses helped predict FCD in two previously unaffected individuals based on their CTG18.1 expansion genotype. CONCLUSIONS. A monoallelic expansion of CTG18.1 contributes to increased disease severity and is causal at (CTG)n>103, whereas a biallelic expansion is sufficient to be causal for FCD at (CTG)n>40. This study highlights the largest contributory causal allele for FCD.",
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author = "Shivakumar Vasanth and Allen Eghrari and Gapsis, {Briana C.} and Jiangxia Wang and Haller, {Nicolas F.} and Stark, {Walter J.} and Nicholas Katsanis and Riazuddin, {Sheikh Amer} and Gottsch, {John D}",
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T1 - Expansion of CTG18.1 trinucleotide repeat in TCF4 is a potent driver of fuchs’ corneal dystrophy

AU - Vasanth, Shivakumar

AU - Eghrari, Allen

AU - Gapsis, Briana C.

AU - Wang, Jiangxia

AU - Haller, Nicolas F.

AU - Stark, Walter J.

AU - Katsanis, Nicholas

AU - Riazuddin, Sheikh Amer

AU - Gottsch, John D

PY - 2015

Y1 - 2015

N2 - PURPOSE. To analyze the expansion of CTG18.1 allele associated with Fuchs’ corneal dystrophy (FCD) in our large cohort of late-onset FCD cases. METHODS. CTG repeats within the CTG18.1 allele were estimated by short tandem repeat (STR) and triplet primed PCR (TP-PCR) assays in our large cohort of 574 late-onset FCD cases and 354 controls and large multigeneration familial cases. The age versus severity relationships were analyzed in FCD genotypes, namely, nonexpanded (N/N), monoallelic expansion (N/X), and biallelic expansion (X/X) with N ≤ 40 CTG monomers. The threshold for causality conferred by an expansion of CTG18.1 was identified by excluding the population of FCD cases who harbored an allele length equivalent to the maximum CTG monomers observed in the controls. RESULTS. The expanded CTG18.1 for (CTG)n>40showed a strong association (P= 1.56 X 10-82) with FCD. Importantly, we delineated the threshold of expansion to 103 CTG repeats above which the allele confers causality in 17.8% of FCD cases. Regression analyses demonstrated a significant correlation between disease severity and age in individuals who harbor either a monoallelic expansion or a biallelic expansion at (CTG)n>40. These analyses helped predict FCD in two previously unaffected individuals based on their CTG18.1 expansion genotype. CONCLUSIONS. A monoallelic expansion of CTG18.1 contributes to increased disease severity and is causal at (CTG)n>103, whereas a biallelic expansion is sufficient to be causal for FCD at (CTG)n>40. This study highlights the largest contributory causal allele for FCD.

AB - PURPOSE. To analyze the expansion of CTG18.1 allele associated with Fuchs’ corneal dystrophy (FCD) in our large cohort of late-onset FCD cases. METHODS. CTG repeats within the CTG18.1 allele were estimated by short tandem repeat (STR) and triplet primed PCR (TP-PCR) assays in our large cohort of 574 late-onset FCD cases and 354 controls and large multigeneration familial cases. The age versus severity relationships were analyzed in FCD genotypes, namely, nonexpanded (N/N), monoallelic expansion (N/X), and biallelic expansion (X/X) with N ≤ 40 CTG monomers. The threshold for causality conferred by an expansion of CTG18.1 was identified by excluding the population of FCD cases who harbored an allele length equivalent to the maximum CTG monomers observed in the controls. RESULTS. The expanded CTG18.1 for (CTG)n>40showed a strong association (P= 1.56 X 10-82) with FCD. Importantly, we delineated the threshold of expansion to 103 CTG repeats above which the allele confers causality in 17.8% of FCD cases. Regression analyses demonstrated a significant correlation between disease severity and age in individuals who harbor either a monoallelic expansion or a biallelic expansion at (CTG)n>40. These analyses helped predict FCD in two previously unaffected individuals based on their CTG18.1 expansion genotype. CONCLUSIONS. A monoallelic expansion of CTG18.1 contributes to increased disease severity and is causal at (CTG)n>103, whereas a biallelic expansion is sufficient to be causal for FCD at (CTG)n>40. This study highlights the largest contributory causal allele for FCD.

KW - Corneal endothelium

KW - CTG18.1

KW - Fuchs’ corneal dystrophy

KW - Repeat expansion

KW - TCF4

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DO - 10.1167/iovs.14-16122

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JO - Investigative Ophthalmology and Visual Science

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