Mutation analysis of the genes associated with anterior segment dysgenesis, microcornea and microphthalmia in 257 patients with glaucoma

Abstract

Genetic factors have an important role in the development of glaucoma; however, the exact genetic defects remain to be identified in the majority of patients. Glaucoma is frequently observed in patients with anterior segment dysgenesis (ASD), microcornea or microphthalmia. The present study aimed to detect the potential mutations in the genes associated with ASD, microcornea and microphthalmia in 257 patients with glaucoma. Variants in 43 of the 46 genes, which are associated with ASD, microcornea or microphthalmia, were available in whole‑exome sequencing. Candidate variants in the 43 genes were selected following multi‑step bioinformatic analysis and were subsequently confirmed by Sanger sequencing. Confirmed variants were further validated by segregation analysis and analysis of controls. Overall, 70 candidate variants were selected from whole‑exome sequencing, of which 53 (75.7%) were confirmed by Sanger sequencing. In total, 27 of the 53 were considered potentially pathogenic based on bioinformatic analysis and analysis of controls. Of the 27, 6 were identified in BEST1, 4 in EYA1, 3 in GDF6, 2 in BMP4, 2 in CRYBA4, 2 in HCCS, and 1 in each of CRYAA, CRYGC, CRYGD, COL4A1, FOXC1, GJA8, PITX2 and SHH. The 27 variants were detected in 28 of 257 (10.9%) patients, including 11 of 125 patients with primary open‑angle glaucoma and 17 of 132 patients with primary angle‑closure glaucoma. Variants in these genes may be a potential risk factor for primary glaucoma. Careful clinical observation and analysis of additional patients in different populations are expected to further these findings.

Spectrum of Genetic Variants Associated with Anterior Segment Dysgenesis in South Florida

“…Our cohort consisted of a unique demographic from South Florida, including large Hispanic and Caribbean populations. Earlier studies focused on European, Asian, African, and Middle Eastern populations [27,28]. We did not identify recurrent variants enriched in our cohort; the difference between ethnicities of our cohort and those of earlier studies does not appear to explain our higher detection rate.…”

“…In this study, we detected potentially causative variants in 42% of probands with ASD, which is higher than the reported proportion, which ranges from 10% to 25% [27]. Table 3 summarizes the characteristics of different genetic studies on ASD.…”

“…We looked at a wide range of ASD conditions, such as Peters anomaly, aniridia, AR syndrome, and PCG. Some other studies focused on a specific phenotype, such as Peters anomaly [23] or primary open-angle glaucoma/primary angle-closure glaucoma [27]. Recognized gene variants for some focused phenotypes are present in smaller portions of affected individuals, which likely contributes to higher detection rate in our study.…”

Genetic Variants Associated with Anterior Segment Dysgenesis in South Florida

“…In this study, we detected potentially causative variants in 42% of probands with ASD, which is higher than the reported proportion, which ranges from 10-25% [27]. Table 3 [27,28].…”

Whole exome sequencing implicates eye development, the unfolded protein response and plasma membrane homeostasis in primary open-angle glaucoma

“…The qualifying variants found in our study were different to the variants associated with microcornea and microphthalmia and unsurprisingly so, as our participants were screened to ensure the absence of any other ocular co-morbidity. Furthermore, one GJA8 variant (p.(Asn190Ser)) has been reported in POAG cases and two CRYBA4 variants (p.(Ser128Phe) and p.(Glu138Gly)) reported in primary angle-closure glaucoma in a Chinese cohort of 257 participants[38]. Other identified eye development genes have roles in neuronal and/or anterior segment development.…”