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Genetic Testing Prevalence, Guidelines, and Pitfalls in Large, University-Based Medical Systems

Ashley E. Neiweem, MD, MHA; Seenu M. Hariprasad, MD; Thomas A. Ciulla, MD, MBA

Seenu M. HariprasadPractical Retina Co-Editor

Seenu M. Hariprasad
Practical Retina Co-Editor

Medical history was made in the fall of 2015 when Spark's SPK-RPE65 phase 3 U.S. Food and Drug Administration (FDA) registration trial showed gains in functional vision and light sensitivity in certain patients with inherited retinal dystrophies (IRDs) such as Leber's congenital amaurosis and retinitis pigmentosa. After more than a decade of work, the results represent the first successful randomized, controlled trial ever completed in gene therapy for a genetic disease in the United States. Since this landmark approval, numerous trials are currently underway investigating the use of other gene therapies to treat a variety of IRDs.

For this column, Ashley E. Neiweem, MD, MHA, and Thomas A. Ciulla, MD, from Indianapolis, Indiana, help to tackle a very important topic — genetic testing in IRD patients. They will provide an overview of genetic testing prevalence, review guidelines, and discuss pearls and pitfalls based on their vast experience.

We are all aware of the obvious barriers to genetic testing, which include cost, complexity at various levels, and unfamiliarity. Numerous educational efforts are underway including those sponsored by the American Academy of Ophthalmology. Unmet needs in terms of education in this landscape will be reviewed in this article.

We are grateful to Drs. Neiweem and Ciulla for generously sharing their extensive knowledge on this topic with our community. I am certain we will all find this piece very educational as it will allow us to better understand the salient issues surrounding genetic testing in retinal diseases.

Ashley E. Neiweem

Ashley E. Neiweem

Thomas A. Ciulla

Thomas A. Ciulla

Introduction

Inherited retinal dystrophies or degenerations (IRDs) comprise a rare group of genetically and phenotypically heterogeneous diseases, ultimately involving progressive photoreceptor dysfunction and subsequent loss of vision.1 Before advances in molecular genetics, patients with IRDs were diagnosed clinically, and before the advent of genetic clinical trials, ordering genetic testing perhaps was a costly endeavor that would not alter management.2 However, increased understanding of molecular and genetic pathways in IRDs has led to clinical trials with potential for targeted therapy, decreased photoreceptor degeneration, and improved visual function.1 Enhanced understanding of genetic testing is increasingly important, as it can facilitate a definitive diagnosis, informing prognosis and management, as well as clinical trial opportunities. Consequently, familiarity with genetic testing assumes increasing importance for the ophthalmologist.

Complexity as a Potential Barrier to Adopting Genetic Testing and Referral

There are more than 260 genes involved in IRDs.3 In addition to providing an accurate molecular diagnosis and identifying potential clinical trial opportunities and treatments, genetic testing can provide information about prognosis and assist in counseling of families, including family member risk assessment. Although only genetic testing can identify the causative gene mutation in IRDs, it may remain unfamiliar to many clinicians in medicine and in ophthalmology because of its complexity. Which patients should receive genetic testing? What tests should I order for the patient? How do I interpret these results? Who will be paying for these tests?

Concerns about the complexity of genetic testing are not unfounded, as the American Academy of Ophthalmology (AAO) Task Force on Genetic Testing defines a genetic test as the sum of five parts: “(1) the clinical determination that a genetic eye disease is likely to be present, (2) the molecular investigation of genomic DNA samples from one or more individuals, (3) the analysis of the resulting molecular data in the context of relevant published literature and public databases using appropriate statistical methods, (4) the interpretation of the data in the context of the clinical findings, and (5) the counseling of the patient about the interpreted findings and their implications.”4 Furthermore, retinal disease genetics demonstrate complexity, due to multiple phenomena: multiple mutations within a given gene (allelic heterogeneity), a given disease that can result from mutations in separate genes (genetic heterogeneity), different clinical phenotypes that result from distinct mutations within a given gene (phenotypic heterogeneity), and dissimilar clinical findings among different individuals for a given mutation (clinical heterogeneity).5

In addition, increasingly complex testing is now available. For example, there is increasing availability and decreasing cost of next-generation sequencing technology, as well as whole exome sequencing, that facilitates testing for multiple genes in a single test, raising the likelihood of a positive result.6,7 However, there is also increasingly likelihood of multiple “variants of uncertain significance,” (VUS) complicating interpretation for physicians.5,8 Specifically, genetic testing results rank each identified mutation based on standards from The American College of Medical Genetics and Genomics (pathogenic, likely pathogenic, VUS, likely benign, benign).8 Pathogenicity is based on numerous elements, including the effect on gene coding, protein structure/function, in vitro/in vivo functional studies, and variant association with clinical disease.8 VUSs pose challenges for clinicians and patients, as they convey a lack of affirmative data of pathogenicity or nonpathogenicity for the identified mutation. A VUS may be reclassified in the future as more information accumulates. Given these and other complexities, the AAO recommends genetic testing only when clinical findings indicate retinal dystrophy that is possibly associated with a genetically identifiable Mendelian disorder, or referral to the appropriate physician or counselor if unfamiliar with such testing.1

Attitudes as a Potential Barrier to Adopting Genetic Testing and Referral

Despite the complexity that clinicians face, genetic testing in general has increasingly been accepted by patients. For example, in a 2017 publication, Chokoshvili et al.9 explored attitudes of the general public of Belgium toward genetics and genetic testing, noting moderate interest in predictive genetic testing with 39.1% of 1,182 respondents willing to learn about their predisposition to diseases. Furthermore, 49.5% indicated an interest in undergoing tests exclusively for treatable or preventable diseases. In retinitis pigmentosa (RP) patients, the acceptance of genetic testing is even higher; in a 2015 study of 48 patients clinically diagnosed with RP, 87% desired genetic testing.10 Clearly, there is desire for genetic testing from patients, but questions remain regarding current providers.

We investigated current attitudes within our department via an institutional review board-approved survey, which was distributed among the resident ophthalmologists, fellows, and attending ophthalmologists in the Department of Ophthalmology at Indiana University. This survey queried respondents about provider demographics, experience, and attitudes toward genetic testing, as well as a variety of potential barriers.9,11 The provider survey suggested numerous potential barriers to adopting genetic testing and referral to a medical genetics clinic, including complexity, interpretability, and cost of genetic testing (Table 1). Despite the real and perceived difficulties that genetic testing implementation can present, current resident ophthalmologists were more likely than attending ophthalmologists to agree that genetic testing was useful in the management of treatable/preventable disease. Furthermore, 93.9% of survey respondents either strongly agreed or agreed with the statement, “I would order genetic testing for a patient to further research about rare inherited diseases where targeted therapy may be helpful in the future.” These results suggest evolving sentiment among the next generation of ophthalmologists, that genetic testing could potentially alter clinical management via available clinical trials.

Survey Results Among Ophthalmology Department Faculty and Residents by Category

Table 1:

Survey Results Among Ophthalmology Department Faculty and Residents by Category

Genetic Testing and Referral During a Recent Ten-Year Span: Results

With precision medicine on the horizon, we investigated the recent past at our institution, representative of a large, university-based health system. To explore actual prevalence of genetic testing for IRD patients within the Indiana University Health system, we conducted a retrospective analysis between December 1, 2008, to December 1, 2018, based on search via relevant billing codes (Table 2). We were interested also in whether additional measured outcomes, including demographics and clinical data, showed any correlation with a referral to a medical genetics clinic or genetic testing (Table 3).

Inherited Retinal Diseases With Corresponding Clinical Diagnosis Codes and ICD-9 and ICD-10 Codes

Table 2:

Inherited Retinal Diseases With Corresponding Clinical Diagnosis Codes and ICD-9 and ICD-10 Codes

Data Collected and Exclusion Criteria

Table 3:

Data Collected and Exclusion Criteria

We found overall that genetic testing was infrequently utilized in IRD care during the past 10 years, with only three of 207 total (1.5%) undergoing genetic testing, directly ordered from an ophthalmologist's office. This figure may seem extraordinarily low to those with expertise in genetic testing or IRDs, but this center is representative of a typical university health care system, without a dedicated IRD clinic and faculty, or IRD-specific research in the recent past. Of those patients who did undergo genetic testing, two of these three patients were father and son, both with clinical findings consistent with Stargardt disease. The third patient, also with clinical findings of Stargardt disease, underwent genetic testing that was negative for pathogenic or likely pathogenic mutations in the ABCA4 gene. Testing in the first two and third patients were ordered by two different retina specialists, both of whom completed training approximately 5 years prior to evaluation. Additionally, testing in these patients was recent, in 2014 and 2017. This timing could relate to the novelty of genetic testing among providers: recently trained specialists might be more inclined to order genetic testing in clinical practice.

Without a dedicated IRD clinic and faculty, referral to medical genetics clinics has meaningful potential to optimize care. However, we found that only a minority of the patients were referred to a medical genetics clinic. Patients 18 years of age or younger or with VA worse than 20/40 were referred more frequently. However, there were no meaningful differences between those referred and not referred in terms of race or ethnicity, insurance plan, or ZIP code distance from the clinic. Unfortunately, only about half of the referred patients (54.5%) completed genetic testing with result; loss to follow up, patient or family refusal, or lack of insurance coverage were contributing factors in approximately 45.5% who did not complete testing even after referral (Table 4).

Results of Retrospective Analysis

Table 4:

Results of Retrospective Analysis

The apparent barriers of cost, complexity, and unfamiliarity with genetic testing over the recent decade at a large university-based teaching institution illustrate unmet need for education in precision medicine. To this end, the AAO has adopted genetic testing modules in its basic science curriculum and recommendations for testing in inherited eye disease. Furthermore, our university medical system has adopted lectures on genetic testing and gene therapy within its grand rounds and lecture schedules. In addition, a multi-specialty board dedicated to genetic testing has since been implemented within the pediatric ophthalmology department. With these and other expanding educational efforts, ophthalmologists will better prepared for the increasing influence of precision medicine in their practices.

References

  1. Duncan JL, Bernstein PS, Birch DG, et al. Recommendations on clinical assessment of patients with inherited retinal degenerations - 2016. American Academy of Ophthalmology. Published June 2016. https://www.aao.org/clinical-statement/recommendations-on-clinical-assessment-of-patients.
  2. Ciulla TA, Hussain RM, Berrocal AM, Nagiel A. Voretigene neparvovec-rzyl for treatment of RPE65-mediated inherited retinal diseases: a model for ocular gene therapy development. Expert Opin Biol Ther. 2020;20(6):565–578. doi:10.1080/14712598.2020.1740676 [CrossRef] PMID:32149547
  3. Daiger SP. RetNet: Summaries of Genes and Loci Causing Retinal Diseases. RetNet. UpdatedMarch26, 2019. https://sph.uth.edu/retnet/sum-dis.htm
  4. Recommendations for genetic testing of inherited eye diseases-2014. American Academy of Ophthalmology. Updated February 2014. https://www.aao.org/clinical-statement/recommendations-genetic-testing-of-inherited-eye-d
  5. Trzupek KM. Where genetic testing fits in the retina practice. Published February 20, 2017. http://www.retina-specialist.com/article/where-genetic-testing-fits-in-the-retina-practice
  6. Wang F, Wang H, Tuan HF, et al. Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements. Hum Genet. 2014;133(3):331–345. doi:10.1007/s00439-013-1381-5 [CrossRef] PMID:24154662
  7. Consugar MB, Navarro-Gomez D, Place EM, et al. Panel-based genetic diagnostic testing for inherited eye diseases is highly accurate and reproducible, and more sensitive for variant detection, than exome sequencing. Genet Med. 2015;17(4):253–261. doi:10.1038/gim.2014.172 [CrossRef] PMID:25412400
  8. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–424.
  9. Chokoshvili D, Belmans C, Poncelet R, et al. Public Views on Genetics and Genetic Testing: A Survey of the General Public in Belgium. Genet Test Mol Biomarkers. 2017;21(3):195–201. doi:10.1089/gtmb.2016.0418 [CrossRef] PMID:28306397
  10. Lee K, Garg S. Navigating the current landscape of clinical genetic testing for inherited retinal dystrophies. Genet Med. 2015;17(4):245–252. doi:10.1038/gim.2015.15 [CrossRef] PMID:25790163
  11. Stone T, ed. ASRS 2016 Preferences and Trends Membership Survey. Chicago, IL: American Society of Retina Specialists; 2016.

Survey Results Among Ophthalmology Department Faculty and Residents by Category

Reasons for Wanting Testing More Likely to Agree/Strongly Agree

Only useful for preventable disease Residents*

Only useful for common disease Male respondents, residents*

Ethical Implications
Positive results causes stress about lifestyle change Comprehensivists
Positive results causes stress about developing the disease Residents*
Positive results will cause guilt due to chance of passing the trait to offspring Female respondents, residents*

Access/Utilization
Worried about the cost of testing Comprehensivists
Worried about result impact on health insurance Comprehensivists
Worried about interpretability of test results Attendings in practice greater than 25 years

Experience
I have offered testing Subspecialists
I have had one or more patients undergo testing Subspecialists
I have found testing to be at least somewhat useful Subspecialists

Inherited Retinal Diseases With Corresponding Clinical Diagnosis Codes and ICD-9 and ICD-10 Codes

Inherited Retinal Disease Diagnosis Code ICD-9 / ICD-10 Codes

Retinitis Pigmentosa (RP) Hereditary Retinal Dystrophy 362.7 / H35.5
Choroideremia (CHM)
Leber's Congenital Amaurosis (LCA)
Cone-Rod Dystrophy (CRD) Hereditary Choroidal Dystrophy 363.5 / H31.2
Stargardt's Macular Degeneration (also known as Juvenile Macular Dystrophy, JMD)

Data Collected and Exclusion Criteria

Data Collected Exclusion Criteria
Demographics Age, gender, race/ethnicity, type of insurance, distance from center to ZIP code of patient's residence Previous diagnosis of non- inherited retinal disease Included but not limited to: retinopathy of prematurity (ROP); age-related macular degeneration (AMD); infectious causes of retinal disease; and vascular or systemic associated retinal diseases (i.e.: diabetic retinopathy, arterial, and vein occlusion

Clinical Data Past medical history, past ocular history, family ocular history, medications
Clinical diagnosis of retinal dystrophy and any treatments performed

Results of Retrospective Analysis

Referred for Testing (n = 33) Not Referred (n = 171)
Completed Testing 18 (54.5%) Completed Testing 0 (0%)
Age 18 years old or younger 30 (90.9%)* Age 18 years old or younger 67 (39.2%)*
Caucasian 27 (81.8%) Caucasian 129 (75.4%)
Medicare/Medicaid 19 (57.6%) Medicare/Medicaid 94 (55.1%)
20/40 or worse in at least one eye§ 15 (75.0%)** 20/40 or worse in at least one eye§ 119 (69.8%)**
ZIP code greater than 50 miles from clinic 18 (54.5%) ZIP code greater than 50 miles from clinic 73 (42.7%)
Authors

Seenu M. Hariprasad, MD, can be reached at University of Chicago, Department of Ophthalmology and Visual Science, 5841 S. Maryland Ave., Room S-439, Chicago, IL 60637; email: retina@uchicago.edu.

Ashley E. Neiweem, MD, MHA, can be reached at SSM Health Davis Duehr Dean Eye Care, 1821 South Stoughton Road, Madison, WI 53716-2257; email: ashley.neiweem@gmail.com.

Thomas A. Ciulla, MD, MBA, can be reached at Vitreoretinal Medicine and Surgery, Midwest Eye Institute, 10300 North Illinois Street, Indianapolis, IN 46290; email: thomasciulla@gmail.com.

Disclosures: Dr. Hariprasad is a consultant or on the speakers bureau for Allergan, Novartis, Biogen, Graybug, EyePoint, Alimera Sciences, Spark, and Regeneron. Dr. Neiweem reports no relevant financial disclosures. Dr. Ciulla is employed by, and has equity in, Clearside Biomedical outside the submitted work.

10.3928/23258160-20201223-02

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