A novel missense TGFBI variant p.(Ser591Phe) in a Finnish family with variant lattice corneal dystrophy

Abstract

Introduction: We describe the phenotype of a variant lattice corneal dystrophy (LCD) potentially caused by a novel variant c.1772C>T p.(Ser591Phe) in exon 13 of the transforming growth factor beta-induced (TGFBI) gene.

Case report: The proband, a 71-year-old woman referred because of bilateral LCD, first seen at the age of 65 years, with recent progressive symptoms, underwent a clinical ophthalmological examination, anterior segment optical coherence tomography and confocal microscopy. Additionally, three siblings and three children were examined. The identified TGFBI variant was screened in six family members using Sanger sequencing. A corneal dystrophy gene screen was performed for the proband. Translucent subepithelial irregularities and central to midperipheral stubby branching corneal stromal lattice lines, asymmetric between the right and the left eye, were visible and resulted in mild deterioration of vision in one eye. Genetic testing revealed a novel variant c.1772C>T in TGFBI, leading to the amino acid change p.(Ser591Phe). One daughter carried the same variant but had only thick stromal nerve fibres at the age of 49 years. The other family members neither had corneal abnormalities nor carried the variant. No keratoplasty is yet planned for the proband.

Conclusions: We classify the novel variant in TGFBI as possibly pathogenic, potentially causing the late-onset, asymmetric variant LCD. Our findings add to the growing number of TGFBI variants associated with a spectrum of phenotypes of variant LCD.

Keywords: Corneal dystrophy; TGFBI; amyloid; lattice corneal dystrophy; pathogenic variant.

Figure 1.

Anterior segment photography and optical coherence topography (AS-OCT) of the proband (II.2). Translucent subepithelial irregularity and stubby branching stromal lattice lines in the right eye (a, b) and similar localized opacities and faint lattice lines in the lower part of the left cornea (c, d). Corneal retroillumination of the right eye (e, f) and left eye (g, h) highlights the deposits. AS-OCT of the right eye shows hyperreflective deposits in the corneal stroma (i) whereas the left cornea is unremarkable (j).

Figure 2.

Corneal confocal images of the right eye of the proband (II.2). The epithelium (a) and the subepithelial nerves (b) are interpreted as normal. Stromal opacities involve mainly the middle (c) and posterior stroma (d). Hyperreflective haze is interpreted as possible stromal scarring. The endothelium is normal (e).

Figure 3.

The pedigree of the family (a). Individuals with an ID number were examined. Plus sign indicates the presence and the minus sign the absence of the TGFBI variant c.1772C>T. Sequence chromatogram of the c.1772C>T variant for the proband and for a non-carrier family member (b). The structure of the TGFBI gene and protein with the localization of the most prevalent TGFBI pathogenic variants, including Ser591Phe (c). Other asymmetric or late-onset lattice dystrophy-associated variants Gly594Val, Asn622Lys, and His626Arg are also shown. The serine residue at position 591 is conserved across species (d; data from the University of California Santa Cruz (UCSC) genome browser).