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

1. Genetic testing of RPE65 for individuals with retinal dystrophy is considered MEDICALLY NECESSARY prior to treatment with Luxturna (voretigene neparvovec-rzyl).

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 a patient’s illness.

2. Genetic testing for macular degeneration and any other ophthalmologic condition is considered NOT MEDICALLY NECESSARY.

3. Whole exome sequencing (WES) or whole genome sequencing (WGS) for ophthalmologic conditions is considered NOT MEDICALLY NECESSARY.

Note 1: For 5 or more gene tests being run on the same platform, such as multi-gene panel next generation sequencing.

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 1 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 (AAO, 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, 2019). 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)

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, 2020). GeneDx has developed many tests including a Glaucoma Panel which tests for 38 glaucoma-related genes (GeneDx, 2018a) and an optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy test which examines 150 genes (GeneDx, 2018b). Invitae has developed the Inherited Retinal Disorders Panel which tests for 248 genes associated with inherited retinal disorders (Invitae, 2020). 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, 2020).

Age-Related Macular Degeneration (AMD)
AMD is an eye condition that causes damage to the central portion of the retina (the macula), impacting the ability to see objects straight ahead. It can lead to complete vision loss and is the leading cause of blindness in industrialized countries (Arroyo, 2020). The two major types of AMD are dry form (atrophic) and wet form (neovascular or exudative). The dry form accounts for 85 to 90 percent of all cases of age-related macular degeneration and typically has a slower progression. Dry AMD is characterized by deposits of drusen under the retina, atrophy of the retinal pigment epithelium, and detachments or clumping of the pigment epithelium. Drusen refers to localized deposits of extracellular material and appears as bright, yellow objects on ophthalmoscopy. The larger and softer variant of drusen is the type seen in AMD. Dry AMD may progress to wet AMD; the risk of dry AMD progressing to wet has been estimated at up to 18% in three years (Arroyo, 2020).

Although accounting for only 10 percent of cases, the wet form results in 80% of legal blindness. Wet AMD, also referred to as choroidal neovascularization, is characterized by growth of abnormal blood vessels into the subretinal space. These vessels leak, which leads to pools of blood or subretinal fluid beneath the retina. This version of AMD often results in rapid loss of central vision (Arroyo, 2020).

AMD 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. Other polymorphisms of CFH and other components of the complement pathway (such as CFB and SERPING1) have also been associated with higher risk of AMD (Arroyo, 2020). 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). 

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 6 and 10 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. 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. Until the benefit of genetic testing can be demonstrated, the AAO task force stated that “the routine genetic testing of patients with complex eye diseases, or unaffected patients with a family history of such diseases, is not warranted.” Further, 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” (AAO, 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” (AAO, 2014).

In 2016, 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 important components of the assessment of patients with IRDs as genetic testing may be valuable to confirm the diagnosis, provide accurate information to the patient and family members and potentially to confirm eligibility to participate in clinical trials” (AAO, 2016).

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).

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).

European Society of Retina Specialists (EURETINA) 
The EURETINA published guidelines for the management of neovascular AMD. These guidelines state that “Doctors should initially ask patients who present with an onset of decreased vision or metamorphopsia, if they have a family history of AMD;” however, genetic testing is not mentioned (Schmidt-Erfurth et al., 2014).

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).

American Optometric Association (AOA) Consensus Panel 
Last reviewed in 2004, the AOA consensus panel published guidelines on the care of a patient with AMD. These guidelines were reviewed by the AOA clinical guidelines coordinating committee. These guidelines do not mention genetic testing for AMD (Cavallerano et al., 1999). These guidelines were reviewed in 2004.

Table of Terminology

References 

1. AAO. (2014). Recommendations for Genetic Testing of Inherited Eye Diseases - 2014 https://www.aao.org/clinical-statement/recommendations-genetic-testing-of-inherited-eye-d 

2. AAO. (2016). Recommendations on Clinical Assessment of Patients with Inherited Retinal Degenerations - 2016. https://www.aao.org/clinical-statement/recommendations-on-clinical-assessment-of-patients

3. AAO. (2019). Age-Related Macular Degeneration PPP 2019. https://www.aao.org/preferred-practice-pattern/age-related-macular-degeneration-ppp

4. Arroyo, J. (2020, June 18). Age-related macular degeneration: Clinical presentation, etiology, and diagnosis. Retrieved March 30 from https://www.uptodate.com/contents/age-related-macular-degeneration-clinical-presentation-etiology-and-diagnosis

5. Avalyon, J. Y., Glenn. (2021). Ocular gene therapy: The next generation. Retina Specialist. https://www.retina-specialist.com/article/ocular-gene-therapy-the-next-generation 

6. Black, G. C., Sergouniotis, P., Sodi, A., Leroy, B. P., Van Cauwenbergh, C., Liskova, P., Grønskov, K., Klett, A., Kohl, S., Taurina, G., Sukys, M., Haer-Wigman, L., Nowomiejska, K., Marques, J. P., Leroux, D., Cremers, F. P. M., De Baere, E., Dollfus, H., & group, E.-E. s. (2021). The need for widely available genomic testing in rare eye diseases: an ERN-EYE position statement. Orphanet journal of rare diseases, 16(1), 142-142. https://doi.org/10.1186/s13023-021-01756-x 

7. Blueprint. (2020). Ophthalmology. https://blueprintgenetics.com/tests/panels/ophthalmology/

8. Cascella, R., Strafella, C., Longo, G., Ragazzo, M., Manzo, L., De Felici, C., Errichiello, V., Caputo, V., Viola, F., Eandi, C. M., Staurenghi, G., Cusumano, A., Mauriello, S., Marsella, L. T., Ciccacci, C., Borgiani, P., Sangiuolo, F., Novelli, G., Ricci, F., & Giardina, E. (2018). Uncovering genetic and non-genetic biomarkers specific for exudative age-related macular degeneration: significant association of twelve variants. Oncotarget, 9(8), 7812-7821. https://doi.org/10.18632/oncotarget.23241 

9. Cavallerano, A. A., Cummings, J. P., Freeman, P. B., Jose, R. T., Oshinskie, L. J., & Potter, J. W. (1999). Care of the Patient withAge-Related Macular Degeneration. https://www.aoa.org/documents/optometrists/CPG-6.pdf

10. Chen, Z. J., Ma, L., Brelen, M. E., Chen, H., Tsujikawa, M., Lai, T. Y., Ho, M., Sayanagi, K., Hara, C., Hashida, N., Tam, P. O., Young, A. L., Nishida, K., Tham, C. C., Pang, C. P., & Chen, L. J. (2020). Identification of TIE2 as a susceptibility gene for neovascular age-related macular degeneration and polypoidal choroidal vasculopathy. Br J Ophthalmol. https://doi.org/10.1136/bjophthalmol-2019-315746 

11. Chew, E. Y., Klein, M. L., Clemons, T. E., Agron, E., Ratnapriya, R., Edwards, A. O., Fritsche, L. G., Swaroop, A., & Abecasis, G. R. (2014). No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements: AREDS report number 38. Ophthalmology, 121(11), 2173-2180. https://doi.org/10.1016/j.ophtha.2014.05.008 

12. Cipriani, V., Lores-Motta, L., He, F., Fathalla, D., Tilakaratna, V., McHarg, S., Bayatti, N., Acar, I. E., Hoyng, C. B., Fauser, S., Moore, A. T., Yates, J. R. W., de Jong, E. K., Morgan, B. P., den Hollander, A. I., Bishop, P. N., & Clark, S. J. (2020). Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration. Nat Commun, 11(1), 778. https://doi.org/10.1038/s41467-020-14499-3 

13. Csaky, K. G., Schachat, A. P., Kaiser, P. K., Small, K. W., & Heier, J. S. (2017). The Use of Genetic Testing in the Management of Patients With Age-Related Macular Degeneration: American Society of Retina Specialists Genetics Task Force Special Report. Journal of VitreoRetinal Diseases, 1(1), 75-78. https://doi.org/10.1177/2474126416680671 

14. Fauser, S., & Lambrou, G. N. (2015). Genetic predictive biomarkers of anti-VEGF treatment response in patients with neovascular age-related macular degeneration. Surv Ophthalmol, 60(2), 138-152. https://doi.org/10.1016/j.survophthal.2014.11.002 

15. García Bohórquez, B., Aller, E., Rodríguez Muñoz, A., Jaijo, T., García García, G., & Millán, J. M. (2021). Updating the Genetic Landscape of Inherited Retinal Dystrophies [Original Research]. Frontiers in Cell and Developmental Biology, 9. https://doi.org/10.3389/fcell.2021.645600 

16. GeneDx. (2018a). Glaucoma Panel. https://www.genedx.com/test-catalog/available-tests/glaucoma-panel/

17. GeneDx. (2018b). Optic atrophy with or without deafness, Ophthalmoplegia, Myopathy, Ataxia, and Neuropathy. https://www.genedx.com/test-catalog/disorders/optic-atrophy-with-or-without-deafness-ophthalmoplegia-myopathy-ataxia-and-neuropathy/

18. 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 

19. Hanany, M., Rivolta, C., & Sharon, D. (2020). Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases. Proceedings of the National Academy of Sciences, 117(5), 2710-2716. https://doi.org/doi:10.1073/pnas.1913179117 

20. Invitae. (2020). Invitae Inherited Retinal Disorders Panel. https://www.invitae.com/en/inherited-retinal-disorders-panel/

21. Lee, K., & Couser, N. (2016). Genetic Testing for Eye Diseases: A Comprehensive Guide and Review of Ocular Genetic Manifestations from Anterior Segment Malformation to Retinal Dystrophy. Genetic Counseling and Clinical Testing 4, 41-48. https://link.springer.com/article/10.1007/s40142-016-0087-0 

22. 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 

23. Luxturna. (2019). Could LUXTURNA® be right for you? https://luxturna.com/about-luxturna/

24. Michalakis, S., Gerhardt, M., Rudolph, G., Priglinger, S., & Priglinger, C. (2021). Gene Therapy for Inherited Retinal Disorders: Update on Clinical Trials. Klin Monbl Augenheilkd, 238(3), 272-281. https://doi.org/10.1055/a-1384-0818 (Gentherapie für erbliche Netzhauterkrankungen: Übersicht zu aktuellen klinischen Studien.) 

25. MolecularVision. (2020). Browse Our Test Menu. https://www.molecularvisionlab.com/mvl-vision-panel/

26. 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 

27. PreventionGenetics. (2020). Stargardt Disease (STGD) and Macular Dystrophies Panel. https://www.preventiongenetics.com/testInfo.php?sel=test&val=Stargardt+Disease+%28STGD%29+and+Macular+Dystrophies+Panel

28. Sangermanoa, R., Scotta, H., Wagner, N., Place, E., & Bujakowska, K. M. (2020). Genetics and Genomics of Eye Diseases: Chapter 14 - Genetic testing of various eye disorders. 

29. Schmidt-Erfurth, U., Chong, V., Loewenstein, A., Larsen, M., Souied, E., Schlingemann, R., Eldem, B., Mones, J., Richard, G., & Bandello, F. (2014). Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA). Br J Ophthalmol, 98(9), 1144-1167. https://doi.org/10.1136/bjophthalmol-2014-305702 

30. Sheck, L. H. N., Esposti, S. D., Mahroo, O. A., Arno, G., Pontikos, N., Wright, G., Webster, A. R., Khan, K. N., & Michaelides, M. (2021). Panel-based genetic testing for inherited retinal disease screening 176 genes. Mol Genet Genomic Med, e1663. https://doi.org/10.1002/mgg3.1663 

31. Singh, M., & Tyagi, S. C. (2018). Genes and genetics in eye diseases: a genomic medicine approach for investigating hereditary and inflammatory ocular disorders. Int J Ophthalmol, 11(1), 117-134. https://doi.org/10.18240/ijo.2018.01.20 

32. 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 

33. 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 

34. 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 

35. 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 2014 Forward