Whole Exome Sequencing identifies multiple pathogenic variants in a large south Indian family with Primary Open Angle Glaucoma

Abstract

Multiple studies have identified several pathogenic variants, majorly contribute to the pathogenesis of primary open-angle glaucoma (POAG). However, these genetic factors can only explain 5-6% of POAG. To identify pathogenic variants associated with POAG by using Whole Exome Sequencing (WES) data of an Egyptian origin of a large family with POAG settled in South India. We recruited a large five-generation family with a positive family history of POAG from Kayalpatanam, Tamil Nadu, India who basically from Egyptian origin. All participants had a comprehensive ocular evaluation (367 study subjects, including 22 POAG and 20 Suspects). We performed WES for 16 samples (9 POAG and 7 controls). We identified one novel potential pathogenic variants, with low-frequency and several pathogenic variants. The heterozygous pathogenic variant c.G3719A in the RPGR-interacting domain of RPGRIP1 gene is segregated in six POAG cases, which may affect the function of RPGR protein complex. In contrast, the RPGRIP1 variant (G1240E) is relatively common in most populations especially in Africans. Furthermore, we identified a novel c.A1295G variant in Rho guanine nucleotide exchange factors Gene 40 (ARHGEF40) and in Retinitis Pigmentosa GTPase regulator (RPGR) gene, may affect the intraocular pressure regulation by altering the RhoA signaling pathway through RPGR protein complex. Moreover, it is difficult to determine the population frequency for this variant. Even though our study reports rare pathogenic variants in multiple genes and pathways associated in the large family with POAG, epigenetic changes and copy number variations may explored to understand the incredibly complexity of the POAG pathogenesis.