Two Likely Pathogenic Variants of COL2A1 in Unrelated Korean Patients With Ocular-Only Variants of Stickler Syndrome: The First Molecular Diagnosis in Korea

Abstract

Stickler syndrome is a genetically heterogeneous disorder that affects the ocular, auditory, and musculoskeletal systems. Ocular-only variant of Stickler syndrome type 1 (OSTL1) is characterized by high risk of retinal detachment without systemic involvement and is caused by alternatively spliced exon 2 mutation of COL2A1. We report the cases of two Korean families with OSTL1 carrying likely pathogenic variants of COL2A1. All patients presented with membranous vitreous anomaly, peripheral retinal degeneration, and/or rhegmatogenous retinal detachment, but no systemic manifestations. By genetic analysis, two likely pathogenic non-exon 2 variants, c.2678dupC (p.Ala895Serfs*49) and c.3327+ 1G>C, were identified in COL2A1. Our results demonstrate that COL2A1 defects in OSTL1 are not confined to mutations in exon 2. Together with molecular data, ophthalmologists should consider genetic diagnosis of Stickler syndrome in patients with vitreous anomaly to prevent blindness from retinal detachment. To our knowledge, this is the first report of genetically confirmed OSTL1 in Korea.

Keywords: COL2A1; Mutation; Ocular-only variant; Retinal detachment; Stickler syndrome.

Fig. 1. (A) Pedigree of family A, harboring the c.2678dupC (p.Ala895Serfs^*49) variant of COL2A1. (B) Wide-field fundus photographs (upper left and right) and fundus autofluorescence photographs (lower left and right) of individual II-3. Bilateral vitreous membrane and radial perivascular retinal degeneration are shown.

Fig. 2. (A) Pedigree of family B, harboring the c.3327+1G>C variant of COL2A1. (B) Wide-field fundus photographs (upper left and right) of individual I-2. Rhegmatogenous retinal detachment with multiple retinal tears is shown in the right eye. Vitreous veil and peripheral perivascular atrophy were found in both eyes. (C) Anterior segment photographs (lower left and right) of individual II-1. Quadrantic lamellar cataract is shown in both eyes.

Fig. 3. Molecular analyses of COL2A1 in two unrelated Korean families with ocular-only variant of Stickler syndrome type 1. (A) Individual II-3 of family A was heterozygous for 1-bp duplication of coding nucleotide 2678, which was predicted to result in frameshift at codon 895 and premature termination at the 49th amino acid in the new reading frame (c.2678dupC; p.Ala895Serfs^*49). (B) Individual I-2 of family B and her son II-1 were heterozygous for the canonical +1 splice site variant (c.3327+1G>C) of COL2A1.