Research

Genetics of Nanophthalmos and Inherited Retinal Degenerations

We seek to identify novel genes and pathways in the pathogenesis of nanophthalmos, a condition characterized by small, but structurally normal eyes. We have recently identified the membrane associated transcription factor myelin regulatory factor (MYRF) as a novel gene in the pathogenesis of this condition.  In a large cohort of nanophthalmos and hyperopia patients, we identified genetic diagnoses in less than 20% of families, leaving 80% of cases currently genetically unexplained despite strong heritability of this condition.  Ongoing efforts include the following:

1. Identifying downstream targets of MYRF and screening them as possible culprits for nanophthalmos and other inherited retinal disease using cutting edge genomic techniques including scRNA sequencing and CUT&RUN sequencing.  

2. Identifying novel candidate genes for nanophthalmos, inherited retinal disease,  and other eye size related phenotypes such as angle closure glaucoma using panel-based, whole exome, and whole genome sequencing from large cohorts of collected patients and families. 

Role of MYRF in retinal pigment epithelial development

Our work with a conditional knockout mouse model of MYRF revealed a role for MYRF in RPE development.  Mice with loss of  Myrf in the early eye field (using Rx>Cre transgene  excision of a floxed Myrf allele) display pigmentation defects in the RPE, loss of photoreceptor outer segment formation, and subsequent retinal degeneration.   Ongoing efforts are aimed at understanding the role of MYRF in RPE development and maintenance at the cellular and molecular level using scRNA sequencing and a combination of histologic, biochemical, and cell biology approaches.  

Genetics of Hereditary Pediatric and Adult Glaucoma

We are using high-throughput sequencing approaches to identify novel candidate genes for pediatric glaucoma, including primary congenital (PCG) and juvenile open angle glaucoma (JOAG). We use a combination of traditional linkage and linkage exclusion analysis along with whole exome and whole genome sequencing to define candidate genes. These will subsequently be validated using cell culture and animal models. A sample pedigree with JOAG is shown along with whole genome linkage exclusion data. 

Role of DDX58 in Glaucoma and Singleton-Merten syndrome

We  recently identified a novel DDX58 variant in several families with Singleton-Merten syndrome, a rare disorder featuring juvenile open angle glaucoma, skeletal defects, aortic calcifications, and a psoriasiform rash.  DDX58 is an RNA-binding protein that serves as a pattern recognition receptor, binding to viral RNA and activating type I interferon signaling as part of the innate immune system.  Variants associated with Singleton-Merten syndrome lead to aberrant activation of this pathway in specific tissues, and there is significant variability.  Ongoing efforts are aimed at generating and characterizing a mouse model of this disorder, and identifying the mechanisms that lead to differential tissue involvement.  

Clinical studies in Ophthalmic Genetic Disorders

Dr. Prasov working together with Pediatric Medical Genetics leads a clinic that specializes in the diagnosis and management of inherited ocular disorders.  We lead and contribute to studies involving new genetic associations, novel disease phenotypes, and genotype-phenotype correlation or natural history.