Discovery of Pigment Dispersion Syndrome and Pigmentary Glaucoma Genes by Exome Sequencing

Project Summary

The goal of this project is to identify genes responsible for pigment dispersion syndrome (PDS) and the related pigmentary glaucoma (PG). Over 50% of patients with PDS develop PG, an aggressive form of glaucoma that is inheritable and mainly affects teenagers and young adults.

The first aim of this study is to find genetic variants that cause PDS using whole exome sequencing (WES). Dr. Fan and colleagues are performing WES for all affected individuals from several large pedigrees affected with PDS. Sequence variants will be filtered using all exomes available for each family by first selecting variants shared among affected members (for each family) and then removing variants present in control exomes. Variants surviving filtering will be prioritized for further evaluation by allele frequency, heterozygosity, conservation, pathogenicity and ocular gene expression.

The second aim is to further evaluate interesting potential disease-causing variants in a PDS/PG patient database. The PDS disease-causing gene(s) identified from Aim #1 will be evaluated in the entire database to determine the overall mutation frequency in a large sample of PDS/PG families, as well as isolated PDS/PG patients. This data will be used to measure the specificity and sensitivity of screening for mutations in the newly discovered PDS-associated gene(s).

PDS is frequently inherited as an autosomal dominant trait. To date, no genes responsible for PDS/PG have been identified in humans. While WES is emerging as the preferred method for gene discovery in Mendelian disorders, this will be the first study to use this cutting-edge technology to find genes responsible for PDS and PG.

Currently there are no treatments for PG other than lowering intraocular pressure which may not be sufficient to avoid permanent blindness. The identification of even one gene for this common form of glaucoma will provide important new information about the underlying molecular events responsible for the disease. Importantly, the knowledge gained could lead to the development of novel methods for other gene-based diagnoses and treatments.