The long-term objectives of the proposed research are to improve our ability to identify the genetic cause of disease for patients with inherited retinal degenerations (IRDs), and to identify genetic modifiers of the severity of IRDs. Accurate genetic diagnosis for patients affected by IRDs is desirable for multiple reasons, including provision of information about potential therapies, disease prognosis, and risk to other family members. This is especially true now that gene augmentation therapy for two genetic forms of IRD has been shown to be safe and effective in early clinical trials. Next-generation sequencing (NGS) based approaches make it possible to sequence all 250+ known IRD disease genes at the same time. Interpretation of the NGS data, and accurate identification of the genetic cause of disease for IRD patients remains difficult, due in part to the highly variable nature of the human genome, and the practice of focusing genetic analyses on genes associated with specific clinical diagnoses, which is sub-optimal due to highly variable and overlapping clinical phenotypes of IRDs. It is hypothesized that the accuracy of genetic diagnoses for IRD patients could be improved through the unbiased assessment of variants in all IRD genes. To make this possible, in Aim 1 it is proposed to perform genetic diagnostic testing of all known IRD genes for a cohort of 4,278 genetically unsolved patients with IRDs for whom longitudinal clinical data is available. The genetic testing will include the analysis of large insertions and deletions. The focus of Aim 2 is discovery and validation of genetic modifiers of IRD disease phenotypes. A consistent observation is that patients with the same genetic cause of IRD can have notably different disease severity. It is hypothesized that variants in other IRD disease genes are the most likely source of influence on disease severity. For these studies, gene-based association testing will be performed using the sequence variants identified in IRD disease genes by the studies in Aim 1 to identify modifiers of disease phenotype. These efforts will be focused initially on patients with selected primary mutations in the three genes that are the most common causes of IRD, RHO, USH2A and RPGR. Preliminary data confirm notable variation in the severity of disease in patients already known to have disease caused by mutations in these genes. Through the proposed genetic studies, we expect to identify at least five separate gene-defect groups, each with 100 patients or more to search for disease modifiers. The activity of candidate modifier alleles identified by these studies will then be tested in zebrafish and on mRNA obtained from patient?s blood or fibroblasts. The proposed research is an essential step toward complete understanding of the complex genetic basis of IRDs that cannot be accomplished by identifying new disease genes alone. The results obtained in these studies will lead to improved diagnostic accuracy, and facilitate development of treatments to limit vision loss from these disorders through identification of pathways that modulate disease severity.

Public Health Relevance

Inherited retinal degenerations (IRDs) are a genetically heterogeneous group of disorders that are important causes of vision loss. The goals of the proposed research are to improve our ability to identify the genetic cause of disease for patients affected by IRDs, and to identify additional genetic features that modify the severity of disease. Finding modifiers that, for example, reduce the severity of disease could help lead to the development of treatments to prevent vision loss from these disorders.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Diseases and Pathophysiology of the Visual System Study Section (DPVS)
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Shen, Grace L
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Massachusetts Eye and Ear Infirmary
United States
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