Whole-exome sequencing identifies multiple pathogenic variants in a large South Indian family with primary open-angle glaucoma

• Published in: Indian journal of ophthalmology 2021-09, Vol.69 (9), p.2461-2468
• Main Authors: Shah, Mohd, Kumaran, Manojkumar, Chermakani, Prakash, Kader, Mohideen, Ramakrishnan, R, Krishnadas, Subbiah, Devarajan, Bharanidharan, Sundaresan, Periasamy
• Format: Article
• Language: English
• Subjects: arghef40 gene; Cilia; DNA sequencing; Eye Proteins - genetics; Familial diseases; Gene frequency; Gene regulation; Genes; Genetic aspects; Genetic diversity; genetic heterogeneity; Genetic variation; Glaucoma; Glaucoma, Open-Angle - diagnosis; Glaucoma, Open-Angle - epidemiology; Glaucoma, Open-Angle - genetics; Guanine; Guanine nucleotide exchange factor; Humans; Intraocular Pressure; Mutation; Nucleotide sequencing; Open-angle glaucoma; primary open-angle glaucoma; RhoA protein; Risk factors; rpgrip1 south indian; Special Focus, Glaucoma, Original; Tonometry, Ocular; Whole Exome Sequencing; Whole genome sequencing
• ISSN: 0301-4738; 1998-3689
• DOI: 10.4103/ijo.IJO_3301_20

Purpose: To identify the pathogenic variants associated with primary open-angle glaucoma (POAG) using whole-exome sequencing (WES) data of a large South Indian family. Methods: We recruited a large five-generation South Indian family (n = 84) with a positive family history of POAG (n = 19). All study participants had a comprehensive ocular evaluation. We performed WES for 16 samples (nine POAG and seven unaffected controls) since Sanger sequencing of the POAG candidate genes (MYOC, OPTN, and TBK1) showed no genetic variation. We used an in-house pipeline for prioritizing the pathogenic variants based on their segregation among the POAG individual. Results: We identified one novel and five low-frequency pathogenic variants with consistent co-segregation in all affected individuals. The variant c.G3719A in RPGR-interacting domain of RPGRIP1 that segregated heterozygously with the six POAG cases is distinct from variants causing photoreceptor dystrophies, reported affecting the RPGR protein complex signaling in primary cilia. The cilia in trabecular meshwork (TM) cells has been reported to mediate the intraocular pressure (IOP) sensation. Furthermore, we identified a novel c.A1295G variant in Rho guanine nucleotide exchange factors Gene 40 (ARHGEF40) and a likely pathogenic variant in the RPGR gene, suggesting that they may alter the RhoA activity essential for IOP regulation. Conclusion: Our study supports that low-frequency pathogenic variants in multiple genes and pathways probably affect Primary Open Angle Glaucoma's pathogenesis in the large South Indian family. Furthermore, it requires larger case-controls to perform family-based association tests and to strengthen our analysis.