Whole Exome Sequencing identifies rare gene variants and pathways in a large south Indian family with Primary Open Angle Glaucoma

Abstract

Purpose : To identify gene variants and pathways associated with Primary Open Angle Glaucoma (POAG) by using Whole Exome Sequencing (WES) data of a large South Indian family.

Methods : We recruited a large five generation South Indian family with positive family history of Primary Open Angle Glaucoma from Kayalpatanam Tamil Nadu, India. All participants had a comprehensive ocular evaluation (367 study subjects including 22 POAG and 20 Suspects). All participants provided written informed consent. The study was performed in accordance with the tenets of the Declaration of Helsinki and approved by the Institutional Review Board of the investigators. We performed Whole Exome Sequencing (WES) for 16 samples (9 POAG and 7 controls). Sanger sequencing was performed to validate pathogenic variants identified.

Results : Prioritization of pathogenic variants using bioinformatics approaches identified multiple gene variants in each sample. Based on case-control enrichment and co-segregation, two novel variants in ARHGEF40 and NCAM1 gene were identified. Three variants in PLK4, KIR2DS4 and SSTR1 were identified through low frequency analysis. Rho guanine nucleotide exchange factors Gene Family protein (ARHGEF12) has been implicated in the risk of glaucoma by increasing intraocular pressure through RhoA/RhoA kinase pathway. In addition, neural cell adhesion molecule (NCAM) participate in the optic nerve changes associated with elevated intraocular pressure. At this time, the precise mechanism ARHGEF40 and NCAM1 remains uncharacterized and requires further study.

Conclusions : Our study presents evidence supporting that multiple gene variants in newly identified genes probably involved in pathogenic pathways of Primary Open Angle Glaucoma as well as segregate in the large South Indian family.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.