Description
Genetic eye diseases involve every part of the eye, including the visual system and ocular adnexa (accessory structures attached to the eye, such as the eyelids, extraocular muscles and orbits); conditions within this group of disorders may be rare or common, and they may exhibit a significant impact on vision or may not affect eyesight at all (Lee & Couser, 2016). Many genes involved in ophthalmologic disorders are now mapped and due to this, scientists have developed a greater understanding of how these genes influence vision and eye health (Singh & Tyagi, 2018).

Regulatory Status
No FDA-approved tests for genetic testing of AMD were found. Additionally, many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare & Medicaid Services (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). As an LDT, the U.S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.

Policy

Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request. 

1. For individuals with clinical signs of an inherited retinal degeneration (see Note 1), single gene or multi-gene panel testing is considered MEDICALLY NECESSARY.
2. For individuals with clinical findings suggestive of other ophthalmologic disorders with a known causative gene(s) where identification of a genetic variant will affect clinical management, testing of the known causative gene(s) is considered MEDICALLY NECESSARY.
3. For individuals with retinal dystrophy, genetic testing of RPE65 prior to treatment with Luxturna (voretigene neparvovec-rzyl) is considered MEDICALLY NECESSARY and is required.

The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of an individual’s illness.

3. Genetic testing for age-related macular degeneration is considered NOT MEDICALLY NECESSARY.
4. For individuals with ophthalmologic conditions, whole exome sequencing (WES) and/or whole genome sequencing (WGS) is considered NOT MEDICALLY NECESSARY.

NOTES:

Note 1: The American Academy of Ophthalmology recommends genetic diagnostic testing for the four major types of inherited retinal degenerations (IRDs):

• Rod-cone degenerations (e.g., retinitis pigmentosa)
• Cone-rod degenerations (e.g., achromatopsia)
• Chorioretinal degenerations (e.g., CHM-associated retinal degeneration [choroideremia])
• Inherited dystrophies that involve the macula (e.g., ABCA4-associated macular degeneration [Stargardt disease])

Note 2: For 5 or more gene tests being run on the same platform, please refer to CAM 235 Reimbursement Policy.

Table of Terminology

Rationale 
 

Approximately 4,000 diseases or syndromes affect humans, and nearly one-third of these diseases are related to the eyes (Singh & Tyagi, 2018). Several ophthalmologic disorders may be inherited, including age-related macular degeneration, cataracts, glaucoma, inherited optic neuropathies, retinitis pigmentosa and Stargardt’s disease (Singh & Tyagi, 2018). Early diagnoses, knowledge of family history and genetic testing can positively influence outcomes and treatment regimens. Inherited retinal diseases (IRDs) affect one in 1380 individuals; it is estimated 36% of healthy people could be considered carriers of at least one IRD-related mutation (Hanany et al., 2020).

Genetic testing for eye disorders is growing in popularity. Further, there is considerable overlap between the clinical phenotypes of many eye disorders, highlighting the importance of genetic testing to determine the cause and most effective treatment avenue (Sangermanoa et al., 2020). To date, genetic tests can identify dozens of ophthalmologic conditions (Stone et al., 2014), and panel tests are already used clinically for early-onset glaucoma, retinal dystrophies, inherited optic neuropathies and more (Wiggs, 2017). Further, many genes have been linked to various human eye diseases and disorders. Table 1 below, adapted from Singh and Tyagi (2018), lists genes and gene variants associated with ten different ophthalmologic conditions. However, it’s also important to recognize that there is a broad clinical spectrum of disorders and many involved genes in IRD-related disorders. Over 270 genes have currently been associated with IRD and the number of genes and heterogeneity of disease is compounded by variations in familial inheritance patterns (García Bohórquez et al., 2021).

Ocular gene therapy shows promise for both inherited and acquired retinal pathologies. Adeno-associated viruses (AAVs) are the most common and leading platform used in retinal gene therapy. These vectors deliver gene-specific approaches to promote expression of a healthy copy of a disease-causing gene (Michalakis et al., 2021). A combination of factors has led to the adeno-associated virus method as the primary vector option for IRDs. First, AAVs have smaller risks of mutagenesis because they aren’t integrated into the host genome. Second, they have low pathogenicity. Lastly, they can transfer genetic material to multiple retinal cell types (Avalyon, 2021). 

Recent advancements in AAV ocular gene therapy have been effective in treating certain types of ophthalmologic conditions. For example, Luxturna – the first Food and Drug Administration approved ocular therapy – is a prescription gene therapy product used to treat patients with inherited retinal degenerations (IRDs) due to mutations in the RPE65 (retinal pigment epithelium-specific 65) gene; however, genetic testing must first be used to determine a potential mutation in this gene (Luxturna, 2022). Therefore, accurate genetic diagnoses have become imperative for some ophthalmologic treatments. 

Other retinal conditions such as choroideremia, achromatopsia, X-linked retinitis pigmentosa, X-linked retinoschisis and AMD are among those being investigated as potential targets for gene therapies using AAVs. In addition, additional viral vectors and non-viral platforms are in the process of consideration because AAVs are limited in the amount of genetic information they can carry, that is, they cannot carry large therapeutic gene sets. For example, larger gene targets (such as the gene associated with Stargardt disease) present a barrier to AAV-specific gene therapy (Avalyon, 2021).

Table 1: Genes/gene variants linked with common human eye diseases/disorders (Singh & Tyagi, 2018)

Age-Related Macular Degeneration (AMD)
Age-Related Macular Degeneration is caused by pathologic changes to the deeper retinal layers of the macula and surrounding vasculature, which can result in central vision loss. There are two main types of AMD: neovascular (“dry” AMD) and nonneovascular (“wet” AMD). Nonneovascular AMD accounts for 80-85% of all cases and generally carries a more favorable visual prognosis, whereas Neovascular AMD affects the remaining 15% to 20% and accounts for approximately 80% of severe vision loss (Thomas et al., 2021). 

Age-Related Macular Degeneration is caused by a combination of genetic and environmental factors. The strongest genetic association is due to genes involved in complement pathways. For instance, a major polymorphism of complement factor H (CFH) and CFH related genes (CFHR1-5) may predispose an individual to AMD (Cipriani et al., 2020). This polymorphism (histidine in place of tyrosine on position 402, CFH Y402H) on chromosome 1 has been associated with higher risk of AMD. One copy of the polymorphism has been associated with a 2.4-4.6 times higher risk of developing AMD whereas both copies of the allele have been associated with a 3.3-7.4 times higher risk. Single nucleotide polymorphisms (SNPs) such as CYP2C19 (G681A) Rs4244285 and CYP1A2 (-163C>A) Rs762551 may also confer added risk for AMD (Stasiukonyte et al., 2017). 

Proprietary Testing
Several genetic tests have been developed to identify ophthalmologic conditions. The MVL Vision Panel (v2) by Molecular Vision tests for 581 genes associated with vision-related inherited conditions (MolecularVision, 2023). GeneDx has developed a Glaucoma Panel which tests for 38 glaucoma-related genes (GeneDx, 2024). Invitae has developed the Inherited Retinal Disorders Panel which tests for 248 genes associated with inherited retinal disorders (Invitae, 2024). Blueprint Genetics has developed 25 different ophthalmology panels which test for over 3,900 genes collectively (Blueprint, 2020). Finally, Prevention Genetics has developed the Stargardt Disease and Macular Dystrophies Panel which tests for 28 relevant genes (PreventionGenetics, 2024).

Clinical Utility and Validity
Lenassi et al. (2019) studied the clinical utility of genetic testing in children with inherited eye disorders. A total of 201 children in preschool (aged 0-5) participated in this study; all participants underwent panel testing. This cohort included “74 children with bilateral cataracts, 8 with bilateral ectopia lentis, 28 with bilateral anterior segment dysgenesis, 32 with albinism, and 59 with inherited retinal disorders” (Lenassi et al., 2019). The diagnostic yield for this study was 64% with testing results leading to altered disease management in 33% of probands (Lenassi et al., 2019).

Fauser and Lambrou (2015) analyzed potential biomarker candidates that could be used in a clinical setting to predict response to anti-vascular endothelial growth factor (anti-VEGF) treatment of neovascular AMD (nAMD). SNPs from 39 publications were evaluated and divided into two categories; those associated with AMD pathogenesis and those targeted by anti-VEGF therapies. The authors found that several studies supported an association between anti-VEGF treatment response and two SNPs, CFH rs1061170 and VEGFA rs699947, but results from randomized controlled trials found no such association (Fauser & Lambrou, 2015).

Chew et al. (2014) determined whether genotypes at two major loci associated with late AMD, complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2), influenced the relative benefits of Age-Related Eye Disease Study (AREDS) supplements; the original AREDs formulation contained vitamins C and E, zinc, copper and beta-carotene. A total of 1237 AREDS participants, 385 with late AMD, were genotyped. Both CFH and ARMS2 genotypes were noted to individually associate with progression to late AMD. However, the investigators found that the genotypes at the CFH and ARMS2 loci did not significantly alter the benefits of AREDS supplements. The investigators concluded that “genetic testing remains a valuable research tool, but these analyses suggest it provides no benefits in managing nutritional supplementation for patients at risk of late AMD” (Chew et al., 2014).

Hagstrom et al. (2015) evaluated the pharmacogenetic relationship between genotypes of SNPs in the VEGF signaling pathway and response to treatment with ranibizumab or bevacizumab for nAMD. For each of the measures of visual equity evaluated, there was no association with any of the genotypes or with the number of risk alleles. The investigators concluded that there are no pharmacogenetic associations between the studied VEGF-A and VEGFR-2 SNPs and response to anti-VEGF therapy (Hagstrom et al., 2015).

Cascella et al. (2018) aimed to characterize exudative AMD in the Italian population and to identify the susceptibility/protective factors (genetic variants, age, sex, smoking, and dietary habits) that are specific for the onset of disease. The study involved a cohort of 1976 subjects, including 976 patients affected with exudative AMD and 1000 control subjects who underwent genotyping analysis of 20 genetic variants known to be associated with AMD. This analysis revealed that eight genetic variants (CFH, ARMS2, IL-8, TIMP3, SLC16A8, RAD51B, VEGFA and COL8A1) were significantly associated with AMD susceptibility. Following a multivariate analysis, considering both genetic and non-genetic data available, age, smoking, dietary habits, and sex, together with the genetic variants, were significantly associated with AMD (Cascella et al., 2018). 

Chen et al. (2020) completed a study of 2,343 Chinese and Japanese individuals including patients with neovascular age-related macular degeneration (nAMD), polypoidal choroidal vasculopathy (PCV) and healthy controls. PCV is a disease of the choroidal vasculature in the eye. The TIE2 (tyrosine kinase, endothelial, TEK) gene was the main focus in this study. In the analysis of all participants, a SNP of the TIE2 gene (rs625767) was significantly associated with nAMD and PCV (Chen et al., 2020).

Strunz et al. (2020) completed a transcriptome-wide association study that included data from 6,144 late-stage AMD cases and 17,832 healthy controls. A total of 10 genes were significantly associated with AMD variants in at least one tissue in this study (27 different human tissues were analyzed). The authors conclude by stating that “our study highlights the fact that expression of genes associated with AMD is not restricted to retinal tissue as could be expected for an eye disease of the posterior pole, but instead is rather ubiquitous suggesting processes underlying AMD pathology to be of systemic nature” (Strunz et al., 2020).

Pontikos et al. (2020) conducted a retrospective study of electronic records in families with molecularly characterized IRD, to investigate proportions with disease attributable to gene variants. It was found that depending on the inheritance pattern, different genes were more likely to be implicated; among all the genes encountered, ABCA4 was most frequent, but when accounting for types of retinitis pigmentosa (RP), the autosomal recessive type was most frequently caused by USH2A whereas autosomal dominant RP was most linked with RHO, RP1, and PRPF31. Additionally, many X-linked retinopathies were the result of variants in RPGR (about 40%). More families in the study’s pediatric cohort were affected by variants in X-linked genes, likely a result of earlier onset and severity of X-linked pathologies and likelihood of earlier diagnoses. The researchers also noted a weak but statistically significant positive correlation with transcription lengths and number of families affected by eye conditions, as longer transcripts are more likely to contain loss of function or premature termination mutations (Pontikos et al., 2020). 

Sheck et al. (2021) reported on the performance of a next-gene sequencing (NGS) panel of 176 retinal genes (NGS 176) in patients with IRD. Among 488 patients, a diagnostic yield of 59.4% was recorded, with younger children being more likely to receive a molecular diagnosis than older adults. The clinical diagnoses were also statistically significantly associated with the diagnostic yield after multivariate analyses. Homogeneous IRD phenotypes of achromatopsia and congenital stationary night blindness, which were associated with six and ten genes, respectively, had diagnostic yields of 100% and 94%, respectively. This study demonstrated the effectiveness of using a new sequencing panel in the UK, and other factors, like age and clinical diagnoses that could correlate with a higher diagnostic yield (Sheck et al., 2021).

García Bohórquez et al. (2021) investigated the genetic basis for IRD in 92 patients using two custom NGS panels. At the time of the study, there were 270 genes associated with IRD. Using NGS, the authors found: among 92 patients, 53 had known gene variants, in 12 patients there was just one mutation in a gene found with a known autosomal recessive pattern of inheritance, and 27 patients (29.3%) had zero specified or identified genes, representing “unsolved” cases. A total of 120 pathogenic or likely pathogenic instances were identified. The most common gene variant was ABCA4. The USH2A gene was the most frequently found gene amongst patients diagnosed with retinitis pigmentosa. Lastly, a total of 10 families had pathogenic variants in more than one IRD-related gene (García Bohórquez et al., 2021).

American Academy of Ophthalmology (AAO) 
In 2014, the American Academy of Ophthalmology (AAO) Task Force on Genetic Testing published recommendations for genetic testing of inherited eye diseases. The Task Force stated that standard clinical diagnostic methods like biomicroscopy, ophthalmoscopy, tonography, and perimetry will be more accurate for assessing a patient’s risk of vision loss from a complex disease than the assessment of a small number of genetic loci. The authors also state that “skilled counseling should be provided to all individuals who undergo genetic testing to maximize the benefits and minimize the risks associated with each test” (Stone et al., 2014). The recommendations include:

• “Offer genetic testing to patients with clinical findings suggestive of a Mendelian disorder whose causative gene(s) have been identified. If unfamiliar with such testing, refer the patient to a physician or counselor who is. In all cases, ensure that the patient receives counseling from a physician with expertise in inherited disease or a certified genetic counselor.
• Use Clinical Laboratories Improvement Amendments-approved laboratories for all clinical testing. When possible, use laboratories that include in their reports estimates of the pathogenicity of observed genetic variants that are based on a review of the medical literature and databases of disease-causing and non–disease-causing variants.
• Provide a copy of each genetic test report to the patient so that she or he will be able independently to seek mechanism-specific information, such as the availability of gene-specific clinical trials, should the patient wish to do so.
• Avoid direct-to-consumer genetic testing and discourage patients from obtaining such tests themselves. Encourage the involvement of a trained physician, genetic counselor, or both for all genetic tests so that appropriate interpretation and counseling can be provided.
• Avoid unnecessary parallel testing — order the most specific test(s) available given the patient’s clinical findings. Restrict massively parallel strategies like whole-exome sequencing and whole-genome sequencing to research studies conducted at tertiary care facilities.
• Avoid routine genetic testing for genetically complex disorders like age-related macular degeneration and late-onset primary open-angle glaucoma until specific treatment or surveillance strategies have been shown in 1 or more published prospective clinical trials to be of benefit to individuals with specific disease-associated genotypes. In the meantime, confine the genotyping of such patients to research studies.
• Avoid testing asymptomatic minors for untreatable disorders except in extraordinary circumstances. For the few cases in which such testing is believed to be warranted, the following steps should be taken before the test is performed: (1) the parents and child should undergo formal genetic counseling, (2) the certified counselor or physician performing the counseling should state his or her opinion in writing that the test is in the family’s best interest, and (3) all parents with custodial responsibility for the child should agree in writing with the decision to perform the test” (Stone et al., 2014).

In 2019, the AAO published the Age-Related Macular Degeneration Preferred Practice Pattern guidelines and state that “The primary risk factors for the development of advanced AMD include increasing age, northern European ancestry, and genetic factors… The routine use of genetic testing is not recommended at this time” (AAO, 2019). In 2023, they reaffirmed that the AAO “does not currently recommend genetic testing for AMD” (Mukamal, 2021).

In 2022, the AAO published recommendations on clinical assessment of patients with inherited retinal degenerations (IRDs). These clinical guidelines state that “Genetic testing and genetic counseling are essential components of the management of patients with IRDs as genetic testing may confirm the diagnosis, provide information to optimize management of the patient and family members, and potentially confirm eligibility to participate in clinical trials.” They also note that “genetic testing for patients with IRDs can take multiple forms, including single gene analyses, panel-based tests that include many IRD disease genes, or more expansive testing such as whole exome and whole genome sequencing. Because of the genetic heterogeneity of the other phenotypes (>80), next generation sequencing testing using a retinal dystrophy panel provides an efficient first step for genetic testing. Whether the patient has syndromic features or not, testing should include genes known to be associated with syndromic forms of retinal disease, since some patients may only show the syndromic features later. Some ‘syndromic genes’ can be associated with a non-syndromic retinal degeneration.” AAO also reiterates the importance of genetic testing for gene therapy: “patients would need to have genetic testing to determine if they are eligible for the FDA-approved voretigene neparvovec or be considered for any of the numerous clinical trials of gene-based therapies” (AAO, 2022). 

European Reference Network for Rare Eye Diseases (ERN-EYE) 
The ERN-EYE released a position statement on the need for eliminating gaps in genetic testing, as collectively, rare eye diseases (RED) are the “leading cause of visual impairment and blindness for children and young adults in Europe.” There are still critical gaps in the administration of genomic testing that need to be addressed, especially in Europe’s smaller countries where no formal genomic testing pathways exist. However, the ERN-EYE emphasizes promoting access to genetic testing to RED and the clinical need and relevance of it with increasing evidence for clinical utility (Black et al., 2021).

American Society of Retina Specialists (ASRS) 
The ASRS states that there is no clinical evidence that changing treatment based on genetic risk is beneficial to the patient. At present there is “insufficient data to support the use of genetic testing in patients with AMD prior to recommendation of current Age-Related Eye Disease Study (AREDS) nutritional supplement use” (Csaky et al., 2017).

Italian IRD Working Group
An interdisciplinary panel of IRD experts convened to discuss IRD. They established parameters surrounding eligibility for RPE65-associated IRD gene therapy. The working group published “a strong consensus” recommendation for the use of “a targeted multi-gene NGS approach, including all the genes known to be responsible for IRDs, both isolated and syndromic forms.” The authors also specify that larger panels such as clinical exome or whole-exome sequencing may also be used. They write, “The use of a larger panel (i.e. either a clinical exome or a whole-exome sequencing) is not excluded but, due to the issue of possible incidental findings, requires a more careful pre-test counselling” (Sodi et al., 2021).

References

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14. Hagstrom, S. A., Ying, G. S., Maguire, M. G., Martin, D. F., Gibson, J., Lotery, A., & Chakravarthy, U. (2015). VEGFR2 Gene Polymorphisms and Response to Anti-Vascular Endothelial Growth Factor Therapy in Age-Related Macular Degeneration. Ophthalmology, 122(8), 1563-1568. https://doi.org/10.1016/j.ophtha.2015.04.024
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18. Lenassi, E., Clayton-Smith, J., Douzgou, S., Ramsden, S. C., Ingram, S., Hall, G., Hardcastle, C. L., Fletcher, T. A., Taylor, R. L., Ellingford, J. M., Newman, W. D., Fenerty, C., Sharma, V., Lloyd, I. C., Biswas, S., Ashworth, J. L., Black, G. C., & Sergouniotis, P. I. (2019). Clinical utility of genetic testing in 201 preschool children with inherited eye disorders. Genet Med. https://doi.org/10.1038/s41436-019-0722-8
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23. Pontikos, N., Arno, G., Jurkute, N., Schiff, E., Ba-Abbad, R., Malka, S., Gimenez, A., Georgiou, M., Wright, G., Armengol, M., Knight, H., Katz, M., Moosajee, M., Yu-Wai-Man, P., Moore, A. T., Michaelides, M., Webster, A. R., & Mahroo, O. A. (2020). Genetic Basis of Inherited Retinal Disease in a Molecularly Characterized Cohort of More Than 3000 Families from the United Kingdom. Ophthalmology, 127(10), 1384-1394. https://doi.org/10.1016/j.ophtha.2020.04.008
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28. Sodi, A., Banfi, S., Testa, F., Della Corte, M., Passerini, I., Pelo, E., Rossi, S., Simonelli, F., & Italian, I. R. D. W. G. (2021). RPE65-associated inherited retinal diseases: consensus recommendations for eligibility to gene therapy. Orphanet journal of rare diseases, 16(1), 257. https://doi.org/10.1186/s13023-021-01868-4
29. Stasiukonyte, N., Liutkeviciene, R., Vilkeviciute, A., Banevicius, M., & Kriauciuniene, L. (2017). Associations between Rs4244285 and Rs762551 gene polymorphisms and age-related macular degeneration. Ophthalmic Genet, 38(4), 357-364. https://doi.org/10.1080/13816810.2016.1242018
30. Stone, E. M., Aldave, A. J., Drack, A. V., Maccumber, M. W., Sheffield, V. C., Traboulsi, E., & Weleber, R. G. (2014). Recommendations for Genetic Testing of Inherited Eye Diseases - 2014. Retrieved 1/29/2015, from https://www.aao.org/clinical-statement/recommendations-genetic-testing-of-inherited-eye-d
31. Strunz, T., Lauwen, S., Kiel, C., Hollander, A. D., & Weber, B. H. F. (2020). A transcriptome-wide association study based on 27 tissues identifies 106 genes potentially relevant for disease pathology in age-related macular degeneration. Sci Rep, 10(1), 1584. https://doi.org/10.1038/s41598-020-58510-9
32. Thomas, C. J., Mirza, R. G., & Gill, M. K. (2021). Age-Related Macular Degeneration. Medical Clinics of North America, 105(3), 473-491. https://doi.org/10.1016/j.mcna.2021.01.003
33. Wiggs, J. L. (2017). Progress in Diagnostic Genetic Testing for Inherited Eye Disease. JAMA Ophthalmol, 135(12), 1385-1386. https://doi.org/10.1001/jamaophthalmol.2017.4957

Coding Section   

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.  

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2024 Forward     

08/14/2024 Annual review, adding coverage criteria #2 for individuals with findings suggestive of other ophthalmologic disorders with a known causative gene(s)  where identification of a genetic variant will affect clinical management, testing of the known causative gene(s) meets medical necessity. Also updating rationale, references and the verbiage of 81404

01012024  NEW POLICY