Comprehensive assessment of genetic variants within TCF4 in Fuchs’ endothelial corneal dystrophy

Eric D Wieben, Ross A. Aleff, Bruce W. Eckloff, Elizabeth J. Atkinson, Saurabh Baheti, Sumit Middha, William L. Brown, Sanjay V. Patel, Jean-Pierre Kocher, Keith Baratz

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

METHODS. Leukocyte DNA was isolated from 68 subjects with FECD and 16 unaffected individuals. A custom capture panel was used to isolate the region surrounding the two previously validated markers of FECD. Sequencing of the TCF4 coding region, introns and flanking sequence, spanning 465 kb was performed at >1000× average coverage using the Illumina HiSequation 2000.

PURPOSE. The single nucleotide variant (SNV), rs613872, in the transcription factor 4 (TCF4) gene was previously found to be strongly associated (P = 6 × 10–26) with Fuchs’ endothelial corneal dystrophy (FECD). Subsequently, an intronic expansion of the repeating trinucleotides, TGC, was found to be even more predictive of disease. We performed comprehensive sequencing of the TCF4 gene region in order to identify the best marker for FECD within TCF4 and to identify other novel variants that may be associated with FECD.

RESULTS. TGC expansion (>50 repeats) was present in 46 (68%) FECD-affected subjects and one (6%) normal subject. A total of 1866 variants, including 1540 SNVs, were identified. Only two previously reported SNVs resided in the TCF4 coding region, neither of which segregated with disease. No variant, including TGC expansion, correlated perfectly with disease status. Trinucleotide repeat expansion was a better predictor of disease than any other variant.

CONCLUSIONS. Complete sequencing of the TCF4 genomic region revealed no single causative variant for FECD. The intronic trinucleotide repeat expansion within TCF4 continues to be more strongly associated with FECD than any other genetic variant.

Original languageEnglish (US)
Pages (from-to)6101-6107
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume55
Issue number9
DOIs
StatePublished - 2014

Fingerprint

Fuchs' Endothelial Dystrophy
Transcription Factors
Trinucleotide Repeat Expansion
Corneal Dystrophy, Fuchs Endothelial, 4
Introns
Genes
Leukocytes
Nucleotides

Keywords

  • Fuchs’ dystrophy
  • Repeat expansion
  • TCF4
  • Transcription factor 4
  • Trinucleotide

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Comprehensive assessment of genetic variants within TCF4 in Fuchs’ endothelial corneal dystrophy. / Wieben, Eric D; Aleff, Ross A.; Eckloff, Bruce W.; Atkinson, Elizabeth J.; Baheti, Saurabh; Middha, Sumit; Brown, William L.; Patel, Sanjay V.; Kocher, Jean-Pierre; Baratz, Keith.

In: Investigative Ophthalmology and Visual Science, Vol. 55, No. 9, 2014, p. 6101-6107.

Research output: Contribution to journalArticle

Wieben, Eric D ; Aleff, Ross A. ; Eckloff, Bruce W. ; Atkinson, Elizabeth J. ; Baheti, Saurabh ; Middha, Sumit ; Brown, William L. ; Patel, Sanjay V. ; Kocher, Jean-Pierre ; Baratz, Keith. / Comprehensive assessment of genetic variants within TCF4 in Fuchs’ endothelial corneal dystrophy. In: Investigative Ophthalmology and Visual Science. 2014 ; Vol. 55, No. 9. pp. 6101-6107.
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abstract = "METHODS. Leukocyte DNA was isolated from 68 subjects with FECD and 16 unaffected individuals. A custom capture panel was used to isolate the region surrounding the two previously validated markers of FECD. Sequencing of the TCF4 coding region, introns and flanking sequence, spanning 465 kb was performed at >1000× average coverage using the Illumina HiSequation 2000.PURPOSE. The single nucleotide variant (SNV), rs613872, in the transcription factor 4 (TCF4) gene was previously found to be strongly associated (P = 6 × 10–26) with Fuchs’ endothelial corneal dystrophy (FECD). Subsequently, an intronic expansion of the repeating trinucleotides, TGC, was found to be even more predictive of disease. We performed comprehensive sequencing of the TCF4 gene region in order to identify the best marker for FECD within TCF4 and to identify other novel variants that may be associated with FECD.RESULTS. TGC expansion (>50 repeats) was present in 46 (68{\%}) FECD-affected subjects and one (6{\%}) normal subject. A total of 1866 variants, including 1540 SNVs, were identified. Only two previously reported SNVs resided in the TCF4 coding region, neither of which segregated with disease. No variant, including TGC expansion, correlated perfectly with disease status. Trinucleotide repeat expansion was a better predictor of disease than any other variant.CONCLUSIONS. Complete sequencing of the TCF4 genomic region revealed no single causative variant for FECD. The intronic trinucleotide repeat expansion within TCF4 continues to be more strongly associated with FECD than any other genetic variant.",
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T1 - Comprehensive assessment of genetic variants within TCF4 in Fuchs’ endothelial corneal dystrophy

AU - Wieben, Eric D

AU - Aleff, Ross A.

AU - Eckloff, Bruce W.

AU - Atkinson, Elizabeth J.

AU - Baheti, Saurabh

AU - Middha, Sumit

AU - Brown, William L.

AU - Patel, Sanjay V.

AU - Kocher, Jean-Pierre

AU - Baratz, Keith

PY - 2014

Y1 - 2014

N2 - METHODS. Leukocyte DNA was isolated from 68 subjects with FECD and 16 unaffected individuals. A custom capture panel was used to isolate the region surrounding the two previously validated markers of FECD. Sequencing of the TCF4 coding region, introns and flanking sequence, spanning 465 kb was performed at >1000× average coverage using the Illumina HiSequation 2000.PURPOSE. The single nucleotide variant (SNV), rs613872, in the transcription factor 4 (TCF4) gene was previously found to be strongly associated (P = 6 × 10–26) with Fuchs’ endothelial corneal dystrophy (FECD). Subsequently, an intronic expansion of the repeating trinucleotides, TGC, was found to be even more predictive of disease. We performed comprehensive sequencing of the TCF4 gene region in order to identify the best marker for FECD within TCF4 and to identify other novel variants that may be associated with FECD.RESULTS. TGC expansion (>50 repeats) was present in 46 (68%) FECD-affected subjects and one (6%) normal subject. A total of 1866 variants, including 1540 SNVs, were identified. Only two previously reported SNVs resided in the TCF4 coding region, neither of which segregated with disease. No variant, including TGC expansion, correlated perfectly with disease status. Trinucleotide repeat expansion was a better predictor of disease than any other variant.CONCLUSIONS. Complete sequencing of the TCF4 genomic region revealed no single causative variant for FECD. The intronic trinucleotide repeat expansion within TCF4 continues to be more strongly associated with FECD than any other genetic variant.

AB - METHODS. Leukocyte DNA was isolated from 68 subjects with FECD and 16 unaffected individuals. A custom capture panel was used to isolate the region surrounding the two previously validated markers of FECD. Sequencing of the TCF4 coding region, introns and flanking sequence, spanning 465 kb was performed at >1000× average coverage using the Illumina HiSequation 2000.PURPOSE. The single nucleotide variant (SNV), rs613872, in the transcription factor 4 (TCF4) gene was previously found to be strongly associated (P = 6 × 10–26) with Fuchs’ endothelial corneal dystrophy (FECD). Subsequently, an intronic expansion of the repeating trinucleotides, TGC, was found to be even more predictive of disease. We performed comprehensive sequencing of the TCF4 gene region in order to identify the best marker for FECD within TCF4 and to identify other novel variants that may be associated with FECD.RESULTS. TGC expansion (>50 repeats) was present in 46 (68%) FECD-affected subjects and one (6%) normal subject. A total of 1866 variants, including 1540 SNVs, were identified. Only two previously reported SNVs resided in the TCF4 coding region, neither of which segregated with disease. No variant, including TGC expansion, correlated perfectly with disease status. Trinucleotide repeat expansion was a better predictor of disease than any other variant.CONCLUSIONS. Complete sequencing of the TCF4 genomic region revealed no single causative variant for FECD. The intronic trinucleotide repeat expansion within TCF4 continues to be more strongly associated with FECD than any other genetic variant.

KW - Fuchs’ dystrophy

KW - Repeat expansion

KW - TCF4

KW - Transcription factor 4

KW - Trinucleotide

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