To date, more than 270 different genes associated with inherited retinal diseases (IRDs) have been identified. Advances in genetic testing are now making it possible to identify the genetic basis of retinal disease in a growing number of patients and, in turn, are leading to more accurate diagnoses and more precise information about prognoses. These advances also create opportunities for a growing number of individuals with IRDs to participate in clinical trials. Retinal Physician talked with Kari Branham, MS, CGC, a genetic counselor from the Department of Ophthalmology and Visual Sciences at the University of Michigan in Ann Arbor, about genetic diagnostic testing, genetic counseling, and how retina specialists and their practices can benefit from forming a partnership with genetic counselors.

Q: IRD research and genetic testing are moving forward at a rapid pace. Are there any misconceptions about genetic testing or genetic counseling that particularly stand out in your mind?

A: Two come to mind right away. First, there are misconceptions about genetic testing being cost prohibitive to patients. In the past, patients either had to pay out of pocket for genetic testing or had to hope that testing would be covered by insurance. Now, with letters of medical necessity, we know that insurance companies may cover the cost of testing. We also are fortunate that we now have several sponsored programs available that will cover the cost of genetic testing. The Foundation Fighting Blindness has an open-access genetic testing program available in which genetic testing is available to patients affected with IRDs at no cost to the patient. Similarly, Spark Therapeutics, which is the manufacturer of the FDA-approved gene therapy treatment Luxturna, offers a no-cost genetic testing program called ID your IRD. These programs have made genetic testing accessible to a greater number of patients.

Another common misconception is that it is always easy to interpret the results of genetic tests. While some genetic testing results may be straightforward, a fairly significant number of results are difficult to interpret. Even when a retina specialist finds the results straightforward, they may be challenging for a patient to understand. A genetic counselor can be valuable through all stages of testing and interpretation and can help patients, and sometimes even clinicians, to understand genetic testing results and their implications.

Q: What are some of the factors that can make interpretation and recommendations difficult?

A: IRDs are associated with extreme phenotypic and genetic heterogeneity. A single IRD may be caused by genetic variants in many different genes, and conversely, variants in a single gene can be associated with multiple IRDs. For example, patients with mutations in the RPE65 gene are most commonly affected with LCA; however, these patients may present with another retinal degeneration, such as early onset retinal degeneration or retinitis pigmentosa. Given this diversity, it may be challenging to identify patients eligible for a particular treatment or trial based on phenotype alone.

Another challenge is variants of unknown significance (VUS). If our group receives inconclusive genetic testing results, it usually means that additional work must be done to determine whether the cause of disease has been identified. In these cases, we may go to the primary literature to see what has been published. We are also very fortunate to have a great team of IRD specialists and genetic counselors with whom we can discuss the results. When we are dealing with a VUS, other members of the family may need to be tested to help determine the pathogenicity of test results. The National Society of Genetic Counselors also has a special interest group for genetic counselors in ophthalmology. This valuable network of genetic counselors around the country can provide input about challenging cases and test results.

Q: How can ophthalmologists, retina specialists, and genetic counselors work together as a team?

A: Some retina specialists may have training in genetics — and in IRDs in particular — but they would be a minority. Although more retinal specialists are recognizing the importance of getting genetic testing done, they may not have the training in genetics to do counseling. It can be very valuable for clinicians to know that they can turn to a counselor who is not only trained to interpret genetic testing but also trained to talk to patients about results that can be difficult for the patient to understand. These are not always easy conversations. There are significant emotional aspects associated with being diagnosed with a genetic condition — we are trained to understand and deal with these emotional aspects.

There are several different models for how a genetic counselor and retina specialist may work together. There are a relatively small number of ophthalmology centers like ours — large academic practices that specialize in IRDs and have genetic counselors who work directly in the clinic. We have a team of 2 genetic counselors and several ophthalmologists who work together to provide comprehensive care to IRD patients. The genetic counselors meet with all patients to obtain family history information, arrange genetic testing, and then meet with the patients after genetic testing to counsel the patients on the results. Other practices at academic medical centers may not have genetic counselors integrated into their clinic, but may have counselors to whom they can refer their patients. Many private practices may not have a genetic counselor directly associated with their clinic, but can similarly refer as needed. Some genetic counselors work in telemedicine and may not regularly work with particular clinicians but are available to see patients anywhere in the country.

Q: A recent paper that you co-wrote[1] mentions 3 major genetic testing initiatives: the eyeGENE research program at NEI and the programs at the Foundation Fighting Blindness and at Spark Therapeutics. How do these programs differ, or what are their highlights?

A: The eyeGENE program at NEI is a nationwide government-sponsored program that enrolled patients for many years to create a repository of valuable clinical and genetic information. They are no longer enrolling patients, but do continue to analyze samples. Both of the other programs — My Retina Tracker and ID your IRD — do large, comprehensive IRD panel testing. Different labs are involved in each program and have slightly different genes available on the panels. Both initiatives are for IRDs only and are only enrolling people from the United States.

Q: Your paper mentions the importance of phenotyping. Could you talk a little about the clinical evaluation or testing that patients should undergo before they are referred to a retinal dystrophy clinic?

A: Extensive phenotyping can provide very important information. Many patients experience what we call a diagnostic odyssey. For example, a child who has decreased vision may first get referred to an optometrist, who can’t correct with glasses, and then subsequently to an ophthalmologist, and then to a retina specialist. Some of these patients will continue to follow with their local retina specialist and others may be referred to an IRD clinic. Some patients may have extensive clinical testing before they come to our clinic and others may not. Typically when a patient comes for a new patient evaluation in our clinic, our clinic will perform an electroretinogram, visual field testing, color vision testing, and photography. Patients will undergo an exam with an IRD specialist and work with the genetic counselor to arrange genetic testing. Many patients who come to see us already have a suspected diagnosis, and typically we will confirm that diagnosis through testing, but some patients will just arrive with unexplained visual loss and no previous testing.

Q: Will patients continue to have a relationship with you after diagnosis?

A: Many patients will continue to have a relationship with their genetic counselor after diagnosis. This may be over the years, as their as lives change, and involve marriage or planning for children, which may cause patients to revisit explanations of the genetic basis for their condition. Similarly, patients will check in over time, to understand more about advances in science that might be applicable to the cause of their disease.

Q: The American Academy of Ophthalmology (AAO) published recommendations on genetic testing[2] in 2014, and they have not yet prepared an update to those recommendations. Are there a few things that you can think of that may have changed since those recommendations were published?

A: While several of the AAO recommendations are still valid today, we have seen significant advances in both the treatments of IRDs and in genetic testing since the original recommendations were published. In 2014, there were no FDA-approved treatments and now, of course, we have Luxturna and multiple other gene-based treatments in clinical trials. The availability of ophthalmic genetic testing has also transitioned from being available primarily in specialized labs in academic medical centers to also being available from larger commercial genetic testing labs that offer ophthalmic testing as part of their genetic testing menus. This expansion of testing has made it so that the section in the AAO document on clinically relevant turnaround time is now not as relevant. Most of the larger clinical testing labs have a turnaround time of approximately 1 to 2 months for large panels and an even shorter turnaround time for targeted tests. Gone are the days when it took 6 months to a year to get results back to patients. The recommendations could also use clarification on ordering large panels. I would still agree that it is not necessary to use whole-genome or whole-exome as first line of testing, but our clinic and many others like ours do use large panel-based testing. The cost of the testing over time has made it so that it is just as cost effective to order a large IRD panel as it is to test for a macular dystrophy or retinitis pigmentosa alone.

The resources for clinicians that are listed in the AAO document are still excellent.[2] Today it is more important than ever to integrate genetic testing and genetic counseling into the clinical care of patients affected with IRDs. Genetic counselors can and do partner effectively with retinal physicians for this optimal care of patients.

References

1. Branham K, Schlegel D, Fahim AT, Jayasundera KT. Genetic testing for inherited retinal degenerations: Triumphs and tribulations. Am J Med Genet C Semin Med Genet. 2020;184(3):571-577. doi:10.1002/ajmg.c.31835
2. AAO Task Force on Genetic Testing. Recommendations for Genetic Testing of Inherited Eye Diseases - 2014. Accessed May 18, 2021. https://www.aao.org/clinical-statement/recommendations-genetic-testing-of-inherited-eye-d