Clinical and Molecular Studies in Families With Inherited Eye Disease

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 patients 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. 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.

- INCLUSION CRITERIA:

To be eligible, the following inclusion criteria must be met, where applicable;

1. Participant must be four years of age or older.

2. Participant must understand and sign the protocol s informed consent document.

3. Individuals or family members of individuals with inherited eye diseases, either
congenital, childhood, or age related.

4. All participants must be able to cooperate with study examination and phlebotomy.

EXCLUSION CRITERIA:

A participant is not eligible if any of the following exclusion criteria are present:

1. Participant has a disease, infection, or trauma that mimic inherited cataracts,
retinal degenerations, glaucoma, etc.

2. Participant has a significant active infection (an infection requiring treatment as
determined by the investigator) or a history of chronic or recurrent infections.

3. Participant requires sedation for study procedures.