Genetic profiling of childhood glaucoma in India

Glaucoma is a clinically and genetically complex disease that is the leading cause of irreversible blindness worldwide. The disease exhibits both complex and Mendelian inheritance with complex disease more common in adult populations and Mendelian forms more common in children and young adults. While recent genome- wide association studies (GWAS) have identified >100 risk loci for adult-onset disease, only 12 genes are known to cause childhood glaucoma, and few studies have targeted this severely affected population. The current set of childhood glaucoma genes can explain only 20% of cases, leaving most affected individuals without a molecular diagnosis after genetic testing. Treatment options for childhood glaucoma cases are limited and these patients are most likely to become blind during their lifetimes, especially in countries such as India where many affected children are not diagnosed. This project will address the significant unmet need of effective genetic testing for childhood glaucoma in India by completing large-scale genetic profiling of affected children to assess the frequency and clinical correlation of causal mutations in currently known genes and to discover novel genes responsible for this devastating disease. This project is a new collaboration between India and U.S. investigators that addresses an important problem for both countries. We will accomplish the following specific aims: 1) Using high quality whole exome sequence (WES) data for 480 childhood glaucoma probands and family members in India we will apply QC metrics and best practice methods to identify rare variants with features expected of pathogenic causal alleles. 2) Using in vitro and in vivo models we will evaluate functional effects of novel childhood glaucoma genes and variants with an initial focus on PLOD2 variants already identified by our Indian colleagues in families with childhood glaucoma.