Clinical and Molecular Studies in Families With Inherited Eye Disease

Background:

Genes are the basic units of heredity. When genes are changed, certain cells don t work like they should. Researchers want to try to better understand the genetic conditions that are linked with inherited eye diseases.

Objective:

To try to identify the genes linked to the development of inherited eye diseases.

Eligibility:

People ages 4 and older who have or have a family member with an inherited eye disease

Design:

Participants will be screened with medical history and medical records.

Participants will have one visit that will take 3-4 hours. This will include:

Medical and family history

Eye exam: This includes the pupil being dilated.

Electroretinography: A small electrode is taped to the forehead. Participants sit in the

dark with their eyes patched for 30 minutes. Then numbing drops and contact lenses are put in

the eyes. They will watch flashing lights.

Blood tests

Saliva sample: They will spit into a container or have the inside of their cheek swabbed.

Genetic testing will be done on participants blood or saliva.

Participants may meet with the researchers to discuss their genetic tests.

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Objective: This project, Clinical and Molecular Studies in Families with Inherited Eye Disease will study inherited eye diseases, both Mendelian and complex age related inherited eye diseases, in families of many nationalities and ethnic backgrounds in order to identify the genes that, when mutated, cause inherited eye diseases and the pathophysiology through which they act. Among the diseases studied will be cataracts, corneal dystrophies and other corneal diseases, retinal degenerations, myopia and other anterior chamber defects, and glaucoma.

Study Population: Families and individuals of many nationalities and ethnic backgrounds. We will study a maximum of 5,000 participants and family members.

Design: The study consists of ascertaining individuals and especially families with multiple individuals, affected by both congenital and age related inherited eye diseases. These participants and their families will undergo detailed ophthalmological examinations to characterize their visual system and determine their affectation status. A blood sample will be collected from each individual for isolation of DNA and in some individuals for lymphoblastoid transformation to establish a renewable source of DNA. Linkage analysis, association analysis, physical mapping, and mutational screening will be carried out to identify the specific gene and the mutations in it that are associated with inherited eye disease in the family. Mutation screening may involve Sanger sequencing if a small number of candidate genes are identified, or whole genome or whole exome sequencing if more genes remain as viable candidates after the initial analysis. If necessary, the gene product will be characterized biochemically. Blood samples may also be used to complete analyses such as: hemoglobin A1c (HbA1c), fasting blood glucose, and glucose tolerance tests. The study will enroll participants at NEI and collaborating institutions.

Outcome Measures: Linkage will be determined using the lod score method, association will be determined using standard statistical procedures to estimate p values, and mutations in specific genes will be assessed using a combination of residue conservation, blosum score, bioinformatic prediction of structural damage to the protein, and molecular modeling. Assessment of biochemical, metabolic, and physiological effects of these mutations will be individualized to the specific case.