Genetic testing for inherited eye conditions in over 6,000 individuals through the eyeGENE network

Abstract

Genetic testing in a multisite clinical trial network for inherited eye conditions is described in this retrospective review of data collected through eyeGENE®, the National Ophthalmic Disease Genotyping and Phenotyping Network. Participants in eyeGENE were enrolled through a network of clinical providers throughout the United States and Canada. Blood samples and clinical data were collected to establish a phenotype:genotype database, biorepository, and patient registry. Data and samples are available for research use, and participants are provided results of clinical genetic testing. eyeGENE utilized a unique, distributed clinical trial design to enroll 6,403 participants from 5,385 families diagnosed with over 30 different inherited eye conditions. The most common diagnoses given for participants were retinitis pigmentosa (RP), Stargardt disease, and choroideremia. Pathogenic variants were most frequently reported in ABCA4 (37%), USH2A (7%), RPGR (6%), CHM (5%), and PRPH2 (3%). Among the 5,552 participants with genetic testing, at least one pathogenic or likely pathogenic variant was observed in 3,448 participants (62.1%), and variants of uncertain significance in 1,712 participants (30.8%). Ten genes represent 68% of all pathogenic and likely pathogenic variants in eyeGENE. Cross-referencing current gene therapy clinical trials, over a thousand participants may be eligible, based on pathogenic variants in genes targeted by those therapies. This article is the first summary of genetic testing from thousands of participants tested through eyeGENE, including reports from 5,552 individuals. eyeGENE provides a launching point for inherited eye research, connects researchers with potential future study participants, and provides a valuable resource to the vision community.

Keywords: gene therapy; genetic testing; inherited retinal disease; rare eye disease.

FIGURE 1

(a) Flowchart describing the case review of eyeGENE participants for genetic screening requisition. The eyeGENE Coordinating Center (CC) reviews the clinical details and family history. Further review is performed by NEI Clinicians. The appropriate genetic test is requested through a Network CLIA laboratory and clinical report returned to the CC. The report is reviewed, and a decision is made to determine if additional testing is warranted. As new tests were developed, older test reports were re-reviewed. (b) Framework of the eyeGENE Network. Referring clinicians submit clinical details and a blood sample for eligible, consenting participants. Clinical data, and genetic data submitted by testing in CLIA laboratories form the eyeGENE Database. Many participants opted to be part of the Registry to be contacted for additional clinical trials. DNA extracted from the blood samples create the eyeGENE Repository. Researchers may request access to samples, data, and to have the Coordinating Center contact Registry participants on their behalf

FIGURE 2

(a) Total count of eyeGENE participants enrolled every year from the start of the program (2006) to the end of recruitment (2015). (b) Average number of genes per test request from 2006 to current

FIGURE 3

(a) Diagnosis of samples sent for testing from eyeGENE to Network CLIA laboratories from 2006 to June 2020. Limited to the top 20 diagnosis counts. (b) Most often reported genes with pathogenic or likely pathogenic variants from 2006 to June 2020. Limited to the top 20 genes

FIGURE 4

Sankey chart depicting variants with interpretations that have been reported inconsistently in the eyeGENE Database over time. The left side shows the first observed interpretation and the right side is the most recently observed interpretation