Discovery of Pigment Dispersion Syndrome and Pigmentary Glaucoma Genes by Exome Sequencing
Pigment dispersion syndrome (PDS) causes pigmentary glaucoma, which is a common form of open-angle glaucoma that usually affects young adults and can be inherited. No genes responsible for this condition have been identified yet in humans. In our proposed research, we will use whole exome sequencing, a new and powerful technology, to find genes that can cause this common form of glaucoma. The results from this project can be used to develop new methods of diagnosis and treatment for PDS and pigmentary glaucoma.
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.
About the Researcher
Dr. Fan’s research so far has yielded 102 publications. His early research resulted in the identification of two new genetic loci on chromosomes 5 (GLC1M) and 15 (GLC1N) that harbor genes predisposing carriers to juvenile-onset glaucoma. This BrightFocus-supported project holds great promise to find at least one gene responsible for pigment dispersion syndrome and pigmentary glaucoma. Moreover, Dr. Fan is currently involved in identifying genetic loci for ocular quantitative traits using South Indian consanguineous pedigrees. He is also involved in analysis of exome data for several different forms of glaucoma. Dr. Fan’s research on glaucoma genetics will provide critical information regarding the biology of the disease, as well as providing the basis for early diagnosis and new treatment.
Lahola-Chomiak AA, Footz T, Nguyen-Phuoc K, Neil GJ, Fan B, Allen KF, Greenfield DS, Parrish RK, Linkroum K, Pasquale LR, Leonhardt RM, Ritch R, Javadiyan S, Craig JE, Ted Allison W, Lehmann O: Lahola-Chomiak AA, Footz T, Nguyen-Phuoc K, Neil GJ, Fan B, Allen KF, Greenfield DS, Parrish RK, Linkroum K, Pasquale LR, Leonhardt RM, Ritch R, Javadiyan S, Craig JE, Ted Allison W, Lehmann OJ, Walter MA, Wiggs JL. Non-Synonymous variants in Premelanosome Protein (PMEL) cause ocular pigment dispersion and pigmentary glaucoma. Hum Mol Genet. 2018 Dec 17. doi: 10.1093/hmg/ddy429. [Epub ahead of print] PubMed PMID: 30561643.
First published on: July 9, 2014
Last modified on: January 11, 2019