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.

The finer details? The predictability of life outcomes from Big Five domains, facets, and nuances

“…If so, this would mirror prevalent observations in the genetics of psychological traits (Plomin & von Stumm, 2018): variation in each of them can be correlated with many thousands of genetic variants, so that even with extremely small and mostly nonsignificant individual effect sizes, collectively they account for a substantial proportion of trait variance. This would also be consistent with the increasing realization that most effect sizes are indeed very small in psychological research (Goetz et al, 2020). Small associations can be addressed with large samples and by testing nuances' collective associations with outcomes rather than focusing on individual trait-outcome associations.…”

“…For example, the associations are generally small in magnitude, particularly when the outcomes are not broad personality-like constructs themselves such as subjective well-being or self-esteem. Although small effect sizes are recognized as a general feature of psychological research, possibly for very good reasons (Goetz et al, 2020), the overall degrees to which outcomes are linked with personality differences may sometimes be underestimated because researchers have rarely explored ways of maximizing personality traits' predictive accuracy; this may require looking beyond the Big Few alone and focusing on the combined predictive value of many traits (Mõttus et al, 2020). Although the best possible prediction from a collection of variables does not necessarily correspond to the strongest possible individual trait-outcome associations because traits partly overlap, often it is exactly the overall degrees to which personality traits and outcomes are linked that researchers care about, rather than the effect sizes of individual traits.…”

Next-Generation Sequencing Applications for Inherited Retinal Diseases

“…Interestingly, 70% of resolved cases were deemed to have causative mutations in 20 genes only [ 82 ]. Similarly, in over 5000 pedigrees with genetic eye conditions from Canada and the US, 68% of pathogenic or likely pathogenic mutations were identified in just 10 genes [ 78 ]. Both of these large studies identified ABCA4 , USH2A and RPGR as the top three genes contributing to IRDs.…”

Introduction to the special issue on Ophthalmic Genetics: Vision in 2020

“…The third and final section highlights translational research efforts to facilitate clinical trials for therapies directed at heritable human disorders. Two research registries in the United States, the National Ophthalmic Disease Genotyping Network (eyeGENE(R); Goetz et al, 2020) and the Foundation Fighting Blindness My Retina Tracker (FFB MRT; Mansfield et al, 2020), describe their respective experiences in large scale genetic testing and association of genotype–phenotype correlations in patient‐and provider‐submitted clinical data. Such registries are critical for better defining variant classification as pathogenic or benign, which in turn defines patient eligibility for gene‐directed therapies.…”