Mutation Analysis of the TGFBI Gene in Consecutive Korean Patients With Corneal Dystrophies

Abstract

Background: Mutations in the transforming growth factor β-induced gene (TGFBI) are major causes of genetic corneal dystrophies (CDs), which can be grouped into TGFBI CDs. Although a few studies have reported the clinical and genetic features of Korean patients with TGFBI CD, no data are available regarding the frequency and spectrum of TGFBI mutations in a consecutive series of Korean patients with clinically diagnosed CDs.

Methods: Patients with any type of CD, who underwent both ophthalmologic examination and TGFBI gene analysis by Sanger sequencing at a tertiary care hospital in Seoul, Korea from 2006 to 2013, were enrolled in this study.

Results: Among a total of 89 patients, 77 (86.5%) were diagnosed as having clinical TGFBI CD. Seventy-three out of 74 patients (98.6%) with granular CD type 2 (GCD2), had the p.R124H mutation. Of particular note, one patient with rapidly progressive CD had the p.R124H mutation as well as a novel nonsense variant with unknown clinical significance (p.A179*). In three patients with lattice CD type 1 (LCD1), one known mutation (p.R124C) and two novel variants (p.L569Q and p.T621P) in the TGFBI gene were identified.

Conclusions: This study provides epidemiological insight into CDs in a Korean population and reaffirms that GCD2 is the most common TGFBI CD phenotype and that p.R124H is the only mutation identified in patients with GCD2. In addition, we broaden the spectrum of TGFBI mutations by identifying two novel missense variants in patients with LCD1.

Keywords: Granular corneal dystrophy type 2; Korean; Lattice corneal dystrophy type 1; Mutation; TGFBI.

Fig. 1. Flow chart of the TGFBI mutation analysis protocol and the results of the 89 patients included in the present study.

^*The p.A179* mutation was additionally found in one patient with the p.R124H mutation; ^†Three patients underwent sequence analysis of only exon 4.

Fig. 2. Sequence electrophoerograms of novel TGFBI variants. (A) The c.535C>T (p.A179*) variant identified in a patient with granular corneal dystrophy type 2 (arrow). (B) The c.1706T>A (p.L569Q) variant identified in a patient with lattice corneal dystrophy, TGFBI type (arrow). (C) The c.1861A>C (p.T621P) variant identified in a patient with lattice corneal dystrophy, TGFBI type (arrow).

Fig. 3. Slit-lamp photographs. (A) Patient with GCD2 without any TGFBI mutations and a few discrete granular deposits in the anterior stroma with unilateral manifestation. (B) Patient with GCD2 carrying a novel p.A179* variant, as well as the p.R124H mutation, with progressed granular opacities in a dense confluent pattern covering most of the corneal surface. (C) Patient with LCD1, carrying the p.L569Q variant and large lattice lines. (D) Patient with LCD1, carrying the p.T621P variant with recurrent corneal erosions with typical lattice lines.