I’m on the phone with the daughter of a patient affected by autosomal dominant TIMP3-associated Sorsby fundus dystrophy, the onset of which is in the fourth or fifth decade of life and vision loss is rapidly progressive.¹ I explain the natural history of the condition to the woman, who’s in her early 20s and considering predictive genetic testing. She has 20/20 vision and reports no signs of retinal disease on her last examination.

As we speak, I concentrate on the inflection of her voice, on high alert for signs of distress. If she tests positive, having this information won’t change her surveillance or management at this moment, but it would allow her to prepare. We carefully and thoroughly delve into the obvious, and the more nuanced, risks, including the possible psychological impact and the limitations of the Genetic Information Nondiscrimination Act (GINA). The testing can be completed using a cheek swab that’s sent to her in the mail—simple, and physically harmless. Over the phone, it can be difficult to build rapport, but I ask her to imagine how she may feel in each scenario; the one in which she tests positive, and the one in which she is negative. I ask her to contemplate how this information will affect not only her, but also others in the family. Although there isn’t currently a treatment for her mother’s condition, the number of clinical trials for inherited retinal diseases is growing, and there’s optimism about targeted therapeutics. I explain that there’s reason to believe this part of our conversation may sound different in a few years.  

After a brief pause, she states that she would like to proceed with testing. There’s no treatment, but the information will make a difference. She explains that she wants to travel, and to have her own children; knowing whether she inherited the TIMP3 variant is a piece that will factor into her timing and decision-making. And if she were positive, she could stay informed about clinical trials and new interventions. Together, we plan to proceed with the test.

Courtesy Getty Images.

Logistically, it’s easier than ever to complete genetic testing. Extracting DNA used to require a blood draw, but now it can be isolated from cheek swabs. Even better, the cheek swabs are nicely packaged in a small cardboard box and delivered to a doorstep along with the next-day Amazon delivery. Several genetic testing panels for ophthalmologic indications are sponsored by pharmaceutical groups, and are therefore “free” to families. Genetic counseling can happen via telehealth, or over the telephone. 

However, the conversation and the decision-making aren’t always linear. The anticipated outcome, or the anticipated feeling about the outcome, may not align when the results are returned. Sometimes, results are extraordinarily complicated, and other times they reveal unexpected information, uncovering new risks, or syndromic diagnoses. That’s the nature of receiving genetic information: The raw human experience remains constant despite our advancements in technology and care. 

Genetic counseling is crucial in this uniquely delicate part of medicine. As access to testing and new technologies surface, the profession must continuously evolve while maintaining the human connectivity at its core. Genetic diagnosis is now a pillar in the model of precision health. As centers move toward patient-centered care, further integration of genetic testing and counseling into practice is inevitable. 

This article will explain how the current approaches to genetic testing work, and take a look at new testing technologies that we may be using in the future.

Genetic Counseling in Retina 

Genetic counselors are allied health care professionals trained to evaluate and discuss genetic testing options, interpret results and communicate with families to facilitate decision-making. Classically housed in prenatal, cancer and pediatric centers, genetic counselors can now be found working in specialty care, including ophthalmology. 

Inherited retinal diseases (IRD) are the some of the most common ocular genetic conditions. There is phenotypic overlap in IRD, which makes genetic diagnosis critical for prognosis and potential treatments as gene therapy and clinical trials continue to emerge. Ophthalmologists specialized in retina need to be able to order and interpret genetic testing accurately to provide essential patient care. In many centers, they work in conjunction with genetic counselors, however, access continues to be limited.² 

At Wills Eye Hospital, we’ve implemented genetic counseling as a standalone service, available to all physicians in every subspecialty. We’re implementing an efficient and cost-effective model of care with the option of telehealth and telephone counseling, as telemedicine appointments have increased in frequency and popularity over recent years.^4,5 This delivery model has also been adopted for the practice of genetic counseling in various subspecialties for residents of Pennsylvania and neighboring states (with plans to expand), since encounters don’t require a physical examination. In ocular genetics, this has been deemed effective and safe, as visual impairment can lead to difficulties with transportation to health-care facilities.⁵ Patients can also be referred for post-test counseling from outside institutions that lack genetic counselor support. Although the number of ocular genetic counselors continues to grow, they’re still relatively hard to come by, and are mostly employed at large ophthalmology centers with specialized care. In 2019, there were fewer than 5,000 genetic counselors in the United States, and very few with expertise in ophthalmology.³  

Whole Exome Sequencing in IRD 

By implementing genetic counseling for each patient undergoing genetic testing on our retina service, we’ve been able to identify candidates for and complete reflex whole exome sequencing (WES) when gene panels are non-diagnostic. Studies show that gene panel-based testing identifies a diagnosis in 70 to 80 percent of cases that are highly suspicious for IRD; however, when researchers completed WES in the remaining families, the yield increased to 92 percent.² Obtaining whole exome sequencing requires careful attention to ordering details and informed consent. When parental testing is included, the diagnostic rate increases further. Therefore, it’s beneficial to organize sample collection and consent with parents or other family members. 

Genetic testing is notoriously expensive and often not covered by insurance. However, with proper prior authorization, affordable self-pay rates, and financial assistance programs, even WES is attainable for most families. 

Gene panel testing isn’t always the best first tier test, nor the only genetic test, needed for each patient with a retinal indication. Gene panel content is undergoing constant updating, to keep up with the ever-changing landscape of molecular diagnosis in retinal diseases. Physical examination that provides detailed phenotypic information along with differential diagnoses is essential to genetic test selection and genetic testing pipelines. Next generation sequencing (NGS) technologies aren’t always validated to perform identification of all types of genetic anomalies. This includes copy number variant analysis and conditions that are caused by trinucleotide repeats, such certain forms of spinocerebellar ataxia, which can be associated with retinitis pigmentosa. 

The interpretation of genetic variants and reporting varies between laboratories. Although two labs may include the same gene on their panel, application of variant classification systems may produce different results and inclusion of variants of uncertain significance can result in discrepancies. 

Genes with pseudogenes and highly repetitive sequences can be difficult for NGS technology to capture. When evaluating gene panels, one must pay close attention to the coverage of these genes, or the ability of the lab to identify variants with the “problem” area. Reading the fine print is necessary when completing genetic testing to avoid missing a diagnosis due to limitations in technology. 

Emerging Technology

Although WES can increase the diagnostic yield in inherited retinal disease, identifying causative genetic results is still imperfect in Mendelian disorders overall.⁶ When using whole genome sequencing (WGS) instead of whole exome sequencing, the yield only increases by a small percentage. There are regions of DNA that are difficult to analyze using the current next-generation sequencing technology (NGS), which performs “short read” sequencing (SRS). 

New technology called long-read sequencing has the potential to capture multiple types of genetic variants, which currently require several genetics tests, in a single NGS based platform. Not only can LRS analyze tandem repeat sequences, segmental duplications, and other areas of the genome that are “problems” for SRS based testing, it can also obtain phase data from sequencing a proband alone (a proband is the first person in a family to bring concern of the genetic condition to a medical professional). Phase data in IRD is extremely valuable, as many of these diseases are autosomal recessive. Targeted testing of parents or children is needed to confirm that two disease causing variants are in trans configuration, or on opposite copies of the gene, as opposed to on the same copy, called cis configuration. Confirming trans configuration is needed to completely confirm a diagnosis. In some cases, phase testing can clarify the meaning of a variant of uncertain significance. However, family members aren’t always available for, or willing to complete, testing. LRS has the potential to change the landscape of genetic testing in retina by removing these extra steps and allowing for a shorter time to diagnosis. Despite this, there are pitfalls, including lower depth of coverage, leading to lower accuracy when compared to short sequencing.⁷ LGS isn’t clinically available currently but is a promising advancement.^6,7

Treatments and Clinical Trials 

When clinicaltrials.gov is searched for “retinitis pigmentosa,” 166 recruiting and soon-to-be recruiting interventional studies are returned. Increasing availability of genotype-specific treatments and clinic trials in inherited retinal disease drives up the demand for genetic services.⁸ This breadth of trials and possible avenues for treatment are vast in comparison to other areas of genetic diagnosis, providing optimism for families and providers alike.

 Increasing availability of trials also presents challenges, as decision-making with respect to determining eligibility and enrollment can be complicated. Genetic counselors may assist, as we often facilitate decision making about genetic testing. This skillset can be applied to clinical trial participation as well. As more clinical trials become available, genetic counselors may increase their knowledge base and change their practice to include discussion on such options. Evaluating eligibility criteria in relation to a patient can also be achieved by a genetic counselor, although input from a physician will continue to be integral. 

On the other hand, we may begin to see the inclusion of genetic counselors on the backend of clinical trial development and enrollment. If a genetic test is necessary to confirm eligibility for patients with specific clinical findings, counselors can ensure the right test is ordered and obtain patient consent. Expertise in genetics and genetic conditions may be invaluable in this setting. 

In conclusion, we finally got the long-anticipated result for the daughter of the patient who was TIMP3-positive. Predictive testing results for known, familial variants in asymptomatic individuals carries a unique amount of weight. As I scroll through the report, I bite my thumbnail, a nervous habit and an uncomfortable reminder of what the patient might feel when I call, though just a fraction as intense. If she’s positive, I’ll wait until the end of a workday to call, and certainly not on a Friday. I’ll set up an appointment to review the results in more detail a few days later. The initial digestion of the information is largely emotional, and questions will often come later once there’s time to process it. Most importantly, I recognize my plan as tentative; I can never fully predict how someone will react, or what they will need. 

I scroll to reveal the remainder of the report: negative. I breathe out. It’s good news. When I call later that day, I get right to the point, and over the phone I hear her exhale in relief. 

Genetic testing will continue to bring us to new places, as we’re able to reach diagnoses more often and faster than ever before. We’ll continue to fill more of our results notes and take-home packets with information on trials and treatments. Our consent conversations will extend to cover new technology with lower cost. But genetic testing will also bring us here, to a place where patient care must be deeply individualized, autonomous and rooted in compassion.

Ms. Procopio is a genetic counselor in the Pediatric Ophthalmology & Ocular Genetics Departments at Wills Eye Hospital. She can be reached at rprocopio@willseye.org.

^{1. Li Z, Clarke MP, Barker MD, McKie N. TIMP3 mutation in Sorsby’s fundus dystrophy: Molecular insights. Expert Rev Mol Med 2005;7:24:1-15.} 

^{2. Lam BL, Leroy BP, Black G, Ong T, Yoon D, Trzupek K. Genetic testing and diagnosis of inherited retinal diseases. Orphanet J Rare Dis 2021;16:1:514.} 

^{3. Stephenson KAJ, Zhu J, Dockery A, Whelan L, Burke T, Turner J, O’Byrne JJ, Farrar GJ, Keegan DJ. Clinical and genetic re-evaluation of inherited retinal degeneration pedigrees following initial negative findings on panel-based next generation sequencing. Int J Mol Sci 2022;23:2:995.}

^{4. Society for Maternal-Fetal Medicine (SMFM). Healy A, Davidson C, Allbert J, Bauer S, Toner L, Combs CA; Patient Safety and Quality Committee. Society for Maternal-Fetal Medicine Special Statement: Telemedicine in obstetrics-quality and safety considerations. Am J Obstet Gynecol 2023;228:3:B8-B17.} 

^{5. Macarov M, Schneider N, Eilat A, Yahalom C. Genetic counseling practice for inherited eye diseases in an Israeli medical center during the COVID-19 pandemic. J Genet Couns 2021;30:4:969-973.} 

^{6. Mastrorosa FK, Miller DE, Eichler EE. Applications of long-read sequencing to Mendelian genetics. Genome Med 2023;15:1:42.} 

^{7. Nakamichi K, Van Gelder RN, Chao JR, Mustafi D. Targeted adaptive long-read sequencing for discovery of complex phased variants in inherited retinal disease patients. Sci Rep 2023;13:1:8535.} 

^{8. Singh M, Tyagi SC. Genes and genetics in eye diseases: a genomic medicine approach for investigating hereditary and inflammatory ocular disorders. International journal of ophthalmology 2018;11:1:117–134.}