Genome sequencing identifies a large deletion at 13q32.1 as the cause of microcoria and childhood‐onset glaucoma

Abstract

Congenital microcoria [MIM# 156600] is an uncommon condition characterized by small pupils (rarely exceeding 2 mm in diameter) that poorly react to mydriatic drops (Fares-Taie et al. 2015). Although unilateral and sporadic cases have been described, the disorder is usually bilateral and autosomal dominantly inherited. Iridocorneal angle abnormalities and axial myopia are detected in most affected individuals, and the disease mechanism involves underdevelopment of the dilator pupillae muscle (Toulemont et al. 1995; Tawara et al. 2005). Recently, heterozygous submicroscopic deletions at 13q32.1 (encompassing the TGDS and GPR180 genes) have been indicated as the cause of congenital microcoria in six families (Fares-Taie et al. 2015). We report clinical and molecular genetic findings in a family segregating glaucoma and congenital microcoria (Fig. 1A). The proband is a 41-year-old male individual who had small, poorly dilating pupils from birth and was diagnosed with glaucoma and iridocorneal angle dysgenesis at age 17 years. He had bilateral trabeculectomies (age 22 years right, age 20 years left) followed by left glaucoma drainage implant insertion (age 34 years) and left cataract surgery with pupil stretch (age 36 years). He is a high myope [−9.75 dioptres spherical equivalent in each eye (prior cataract surgery)] and is not using any ocular/systemic medications. Notably, his mother, who also has small pupils, was diagnosed with glaucoma at age 20 years, and his daughter (age 6 years; Fig.1B), sister (age 44 years) and nephew (age 7 years) have microcoria without glaucoma (Fig. 1A). Examination at age 41 years revealed visual acuity of 0.18 logMAR right and 0.28 logMAR left. The intraocular pressure was 13 mmHg in each eye. The axial length was 25.01 and 26.16 mm in the right and left eye, respectively. Gonioscopy revealed iris processes over the trabecular meshwork bilaterally (Fig. 1C). Peripheral iris transillumination defects and a featureless iris surface with poorly developed collarettes and crypts were observed. The pupil diameter in mesopic conditions was <2.0 mm, and the pupils failed to dilate with topical mydriatics (Fig. 1D). There was bilateral optic disc cupping, and visual field testing revealed a superior field scotoma in the right eye and extensive inferior and superior visual field loss in the left eye. As the proband was keen to clarify the risks to his children, genetic testing was offered. After informed consent was obtained, a blood sample was tested using clinical genome sequencing. The Complete Genomics (California, USA) platform was used, and bioinformatics analysis was performed using the Complete Genomics pipeline (v2.5) (Carnevali et al. 2012). After excluding mutations in known glaucoma-associated genes, we focused on the 13q32 region, where an autosomal-dominant microcoria gene has been mapped (Fares-Taie et al. 2015). A heterozygous 69-kb deletion (chr13:95219283-95288376) encompassing the entire TGDS and GPR180 genes was detected. The presence and extent of the deletion were confirmed through Sanger sequencing of the deletion breakpoints. A family with early-onset glaucoma and microcoria, in which genome sequencing identified a large genomic deletion, is reported. It is evident from previous studies that individuals with congenital microcoria are at risk of developing ocular hypertension (Toulemont et al. 1995; Tawara et al. 2005; Fares-Taie et al. 2015). This rarely occurs before the end of the second decade of life, but at least one in three microcoria patients are going to require treatment for glaucoma (Toulemont et al. 1995). It can be speculated that glaucoma in these cases is associated with the iridocorneal angle abnormalities. However, the gonioscopic appearance in the proband of this study was similar to that of his older sister who has microcoria without any signs of glaucoma at age 44. Similar findings have been previously reported (Toulemont et al. 1995) suggesting that the significance of the angle dysgenesis is unclear. Sequencing of the entire genome for clinical applications has now entered medical practice (Biesecker & Green 2014). The rapid identification of the disease-causing Deoxyribonucleic acid (DNA) sequence alteration in the presented case clearly demonstrates the potential of this approach in the diagnostics of developmental eye disorders.