Democratization of genetic screening for inherited retinal degenerations: Historical context and new challenges

Paul Yang does not have conflicts to declare.

Over the past 10 years, the availability, accessibility, and breadth of genetic testing for inherited retinal degenerations (IRD) have improved greatly beyond all expectations. Previously, genetic testing was only available on a limited basis via ophthalmic geneticists at select tertiary care centers. Even then, testing typically amounted to a single gene test or a handful of genes that fit the suspected phenotype as determined by the ophthalmic geneticist. As our knowledge of the various genes associated with IRDs grew exponentially, the techniques for genetic testing evolved to make large panel testing practical and feasible using Next Generation Sequencing.

As these large panel genetic tests for IRD grew from 50 to 100 genes to >300 genes currently, they became useful not only for confirming the clinical diagnosis of classic phenotypes, but also an important tool for discovering novel phenotype-genotype correlations. Now there are multiple commercial laboratories that offer an array of large panel genetic tests. With the ability to conduct large-scale genetic testing of IRD patients, we are now better able to appreciate the complexity of the phenotype correlations for genetic variants of different pathogenicity within a given gene. For example, in autosomal recessive IRDs wherein bi-allelic pathogenic variants are required to cause disease, it has been shown that low pathogenic variants can modify the severity and phenotype of the disease. This has been demonstrated in Stargardt disease, wherein hypomorphic variants in the ABCA4 gene can dictate the severity of the associated retinal degeneration and prognosis (Lee et al., 2022).¹ The CLN3 gene is another good example wherein distinct biallelic variants can either cause a devastating and lethal condition, juvenile neuronal ceroid lipofuscinosis (Batten disease), or an isolated (non-syndromic) retinal degeneration (Smirnov et al., 2021; Mizobuchi et al., 2020; Chen et al., 2019; Ku et al., 2017).2, 3, 4, 5

In the past, accessibility to these large panel tests was also limited due to poor payer coverage, but now some labs have partnered with sponsors to offer no-cost testing that can be ordered by community ophthalmologists based on an IRD diagnosis or symptomology. The democratization of genetic testing will hopefully enfranchise IRD patients to better understand their disease, inheritance risk to other family members, and eligibility for relevant clinical trials. However, a hidden challenge is that genetic test results are not always definitive and require proper interpretation by an ophthalmic geneticist to determine the likelihood that a given result explains the phenotype in question. Genetic counselors are invaluable allies in this endeavor. Even in cases of classic IRDs, it is still possible for the genetic test results to be negative or equivocal because our knowledge of causative genes is incomplete and the genetic testing/analysis methods are still evolving. Moreover, the pre-test probability that a patient actually has an IRD will affect the yield and utility of the genetic test results. The complexity of ophthalmic genetics and the breadth of knowledge required to establish novel genotype-phenotype correlations in atypical cases often requires the collaboration of ophthalmic geneticists, genetic counselors, and retina specialists, as well as uveitis specialists for cases that exhibit signs of past or current ocular inflammation.

The case report by Honasoge and Smith, 2022,⁶ illustrates the pitfall of large panel genetic testing for IRDs. As explained by Dr. Smith in his reply to the criticism on his report, it is unlikely that a mono-allelic variant in CLN3 would be disease-causing and the phenotype is better explained by non-genetic etiology. We hope that this case serves as a valuable tool for better understanding the pros and cons of genetic testing. Prior to genetic testing, it can be useful to garner second and third opinions on cases with atypical presentation or disease history to optimize pre-test probability. When in question, it is always a good idea to refer patients with suspected IRD to an ophthalmic geneticist, who can make the final decision on genetic testing for challenging cases and provide appropriate interpretation and counseling of the test results.

To properly respond to these challenges at AJO Case Reports, we have implemented a new work flow to consistently process all manuscripts that contain reports of genetic test results. In addition to the usual peer-review process, a new layer of internal review by dedicated genetic specialists will be implemented to ensure all genetic results are reported according to accepted standards and ACMG-AMP guidelines (the expected reporting standards are now published online at AJO Case Reports). The goal is to guard against the unintentional misinterpretation of genetic test results that are either inconclusive or insufficient to cause disease.

Supported by Foundation Fighting Blindness TA-NMT-0521-0803-OHSU-TRAP (Columbia, MD), P30 EY010572 from the National Institutes of Health (Bethesda, MD), and unrestricted departmental funding from Research to Prevent Blindness (New York, NY).