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Whole Exome Sequencing and Segregation Analysis Confirms That a Mutation in COL17A1 Is the Cause of Epithelial Recurrent Erosion Dystrophy in a Large Dominant Pedigree Previously Mapped to Chromosome 10q23-q24

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Whole Exome Sequencing and Segregation Analysis Confirms That a Mutation in COL17A1 Is the Cause of Epithelial Recurrent Erosion Dystrophy in a Large Dominant Pedigree Previously Mapped to Chromosome 10q23-q24

Benjamin R Lin et al. PLoS One.

Abstract

Purpose: To report identification of a COL17A1 mutation in a family with a corneal dystrophy previously mapped to chromosome 10q23-q24.

Methods: Whole-exome sequencing was performed on DNA samples from five affected family members and two unrelated, unaffected individuals. Identified variants were filtered for those that were: located in the linked interval on chromosome 10q23-q24; novel or rare (minor allele frequency ≤0.01); heterozygous; present in all affected individuals and not in controls; and present in genes that encode proteins expressed in human corneal epithelial cells (reads per kilobase per million ≥1). Sanger sequencing of identified variants (SNVs) was performed in additional family members. In silico analysis was used to predict the functional impact of non-synonymous variants.

Results: Three SNVs located in two genes were identified that met the filtering criteria: one rare synonymous c.3156C>T variant in the collagen, type XVII, alpha I (COL17A1) gene; and two rare variants, one synonymous and one missense, in the dynamin binding protein (DNMBP) gene. Sanger sequencing of additional family members determined that only the COL17A1 variant segregates with the affected phenotype. In silico analysis predicts that the missense variant in DNMBP would be tolerated.

Conclusions: The corneal dystrophy mapped to chromosome 10q23-q24 is associated with the c.3156C>T variant in COL17A1. As this variant has recently been identified in five other families with early onset recurrent corneal erosions, and has been shown in vitro to introduce a cryptic splice donor site, this dystrophy is likely caused by aberrant splicing of COL17A1 and should be classified as epithelial recurrent erosion dystrophy.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Pedigree of a family with chromosome 10q23-q24 linked dystrophy.
Females are represented by circles, males by squares, and individuals of unknown gender by diamonds. Affected individuals are shown with filled symbols and unaffected individuals are shown with open symbols. Individuals of unknown affected status are shown with a question mark. The arrow head indicates the proband. An asterisk (*) indicates individuals that underwent WES. A dagger (†) indicates individuals that underwent Sanger sequencing for identified candidate variants in COL17A1 and DNMBP.
Fig 2
Fig 2. Clinical features of chromosome 10q23-q24 linked dystrophy.
A. Affected individual V-2 (28 years old) demonstrates a clear cornea in the right eye. B. Three months later, she developed a corneal erosion (arrows). C. Affected individual V-3 (24 years old) also demonstrated clear corneas prior to the development of a corneal erosion, the location of which can be identified by the opacification of the corneal epithelium (arrows). D. Affected individual IV-1 (72 years old) demonstrates diffuse subepithelial opacification secondary to chronic recurrent corneal erosions seen with slit and diffuse illumination in the right (D and E) and left (F) eyes.

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