Genes and mutations causing at least 25% of cases of autosomal dominant retinitis pigmentosa (adRP) remain unknown. This is a major barrier to diagnosis and treatment.
The aims of this application are to identify the remaining adRP genes and to use this information to impact clinical care for patients and families. This is a Program Goal of the NEI. AdRP and related diseases affect more than 30,000 Americans and are a leading cause of loss of vision in young adults. Symptoms include progressive retinal degeneration and characteristic retinal abnormalities leading to legal or complete blindness. Although these are single-gene disorders in individuals, as a group of diseases they are highly heterogeneous with many genes, mutations and clinical phenotypes. In prior research we enrolled and tested more than 800 adRP families and identified six new adRP genes. The enrolled families include a well-defined AdRP Cohort of 266 families with extensive sequencing, linkage and molecular testing.
Specific Aim 1. We have identified mutations in 76% of Cohort families, leaving 62 without mutations in known genes.
The first Aim i s to find the disease-causing gene and mutation in these families. This will identify new adRP genes.
Specific Aim 2. Among the adRP families not in the Cohort, conventional testing has failed to detect the mutation in over 300.
The second Aim i s to apply advanced DNA testing methods to these families. This will identify novel mutations and establish a replication sample for new genes detected in Aim 1. This will also contribute to a better understanding of the relationship between mutations and clinical outcome (genotype/phenotype).
Specific Aim 3. During the project we will continue to enroll new adRP families through our clinical collaborators, roughly 75 per year. Although the majority of these families will have known mutations, a fraction will have novel genes.
The third aim i s to add the families with potential novel genes to the families in Aims 1 and 2. Methods for Specific Aims include retinal-capture next-generation sequencing (NGS), Sanger confirmation of mutations in our CLIA-certified DNA Diagnostic Laboratory, whole-genome and fine-structure linkage mapping, whole-exome and whole-genome NGS, and extensive bioinformatic analysis. The most difficult problem in medical genetics today is determining which of the many potentially-pathogenic variants in each of us is actually pathogenic in a patient. We will address this problem with segregation analysis, replication in other patients, data sharing with collaborating laboratories, development of an extensive retinal-gene variant database, and biochemical assays. For patients, the immediate impact of this project is improved diagnosis and counselling for retinitis pigmentosa. Further, knowing the underlying cause of disease, the genotype, is an essential requirement for enrolling in most clinical trials. More broadly, identification of novel genes and mutations will contribute to a beter understanding of pathogenesis and may reveal new targets for treatment.
This project will directly impact clinical care for patients with inherited, blinding diseases of the retina; may reveal novel targets for drug therapy; and will continue to identify genotype-known patients to enroll in current and future gene therapy trials. Finding new genes causing retinitis pigmentosa and related diseases will contribute to a better understanding of the normal biology of vision. Finally, the methods and information developed for these specific diseases are likely to assist in understanding and treating a broad range of other inherited and acquired eye diseases.
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