Whole Exome and Whole Genome Sequencing for Genotyping of Inherited and Congenital Eye Conditions

Objective: The objective of this study is to identify genetic causes of inherited eye conditions through whole exome or whole genome sequencing (referred to as exome sequencing and genome sequencing in the remainder of the document). This includes identifying mutations in known genes or novel genes for recognized conditions, as well as identifying mutations in novel genes for previously uncharacterized genetic conditions involving the eye.

Study Population: We plan to recruit 2,000 participants, to include both participants with an eye condition under study and unaffected family members. Ideally unaffected family members will be parents of an affected participant.

Design: Participants will be self-referred or referred by an outside clinician. They will preferably be evaluated at the National Institutes of Health (NIH), but the option to participate offsite will be offered. Participants evaluated onsite will be recruited through other pre-existing NIH protocols, such as the National Eye Institute (NEI) Screening protocol (08-EI-0102), the NEI Ocular Natural History protocol (16-EI-0134), the Genetics of Inherited Eye Disease protocol (15-EI-0128), and the Pathogenesis and Genetics of Microphthalmia, Anophthalmia and Uveal Coloboma (MAC) protocol (13-EI-0049).

Offsite participants will be screened via phone or secure videoconference, and records will be requested for evaluation of affected participants. Both affected and unaffected eligible participants will undergo genetic counseling and will provide a blood sample and/or saliva sample for exome or genome sequencing. Biological relationships will be confirmed prior to exome or genome sequencing. Sequence data will be analyzed for primary variants and secondary findings, unless participants choose to opt-out of secondary analysis and reporting. All sequence variants deemed clinically relevant will be validated in a Clinical Laboratory Improvement Amendment (CLIA)-certified laboratory. The results will be returned to the participant in-person, secure videoconference, or by telephone.

Outcome Measures: This is an etiologic study that will generate molecular information about previously-recognized conditions for which participants did not have a molecular diagnosis, as well as molecular information for previously uncharacterized conditions involving the eye.

• INCLUSION CRITERIA:

To be eligible, participants must meet the following criteria:

• Participant is affected with an eye condition under study or is a family member of an affected individual who will be informative for ES/GS analysis and interpretation.
• Participant or legally authorized representative (LAR) of participant understands and signs the informed consent document.

Exclusion criteria

• Participants who cannot comply with study procedures are ineligible.
• Participants who are minors are ineligible if they do not have a parent/LAR who can consent and make decisions on their behalf. Participants who are or become decisionally impaired are ineligible if they do not have, or are unable to obtain, a legally authorized representative who can consent and make decisions on their behalf.
• Participants who are minors and under joint custody are ineligible if parents disagree about study participation.
• Prospective participants or their parent/LAR who, based on the judgment of the team, appear to have impaired ability to understand and appropriately use complex medical and genetic information, or to cope with potentially life altering medical information, will be ineligible.