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

Study Overview
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Brief Summary
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Objective: The objective of this study is to identify genetic causes of inherited eye conditions through whole exome or whole genome sequencing. 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 1,685 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: Most affected participants will be recruited from existing studies at the NEI. These include, but are not limited to, the 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) study (13-EI-0049). Unaffected family members will be invited to participate once an affected relative is determined eligible for participation. Offsite affected and unaffected participants will also be enrolled. If a participant is self-referred or referred to the study by an outside provider, screening will determine whether participation is offered. 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 may 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 CLIA-certified laboratory and the results will be returned to the participant in-person, secure video conference, 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.

Detailed Description
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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 1,685 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 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 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 CLIA-certified laboratory and the results will be returnedto 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.

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

Conditions
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Genetic Eye Disease

Participation Criteria
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Eligibility Criteria
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INCLUSION 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 legal guardian of participant understands and signs the informed consent document. EXCLUSION CRITERIA Participants who cannot comply with study procedures are ineligible. Participants who are minors or participants who are adults and are decisionally impaired are ineligible if they do not have a legal guardian who can consent and make decisions on their behalf. Documentation of legal guardianship must be provided for decisionally impaired adults. Participants who are minors and under joint custody are ineligible if parents are in disagreement about study participation. Prospective participants or their legal guardians 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.

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Affected participants<br>Participants with an eye disease. | |
| Unaffected family members<br>Unaffected family members. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| This is an etiologic study that will generate new genes or variants for inherited eye diseases. | 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 eye conditions. | Until the affected participant has received confirmed Primary Results (PRs). Unaffected family members may or may not receive any results, but their participation will be ongoing until their affected family member receives PRs. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Whole Genome Sequencing, Genetic Eye Disease, Natural History