CAM 204103

Genetic Testing for Macular Degeneration

Category:Laboratory   Last Reviewed:July 2019
Department(s):Medical Affairs   Next Review:July 2020
Original Date:January 2014    

Description
Age-related macular degeneration (AMD) is a complex disease involving both genetic and environmental influences. Testing for mutations at certain genetic loci has been proposed to predict the risk of developing advanced AMD. AMD is divided into the dry form, associated with slowly progressive vision loss, and the wet form, which may be associated with rapidly progressive and severe vision loss. The risk of AMD and of the development of the wet form is associated with genetic and nongenetic (e.g., age, smoking) influences.

The evidence for genetic testing in individuals who are asymptomatic with risk of developing AMD includes genetic association studies and risk prediction models. Relevant outcomes are test validity, change in disease status and functional outcomes. The analytic validity of genetic testing for AMD is high, and the clinical validity of genetic testing appears to provide a small, incremental benefit to risk stratification based on nongenetic risk factors. The clinical utility of genetic testing for AMD is limited, in that there are currently no preventive measures that can be undertaken. No studies have shown improvement in health outcomes in patients who have been identified as being at high risk based on genetic testing. The evidence is insufficient to determine the effects of the technology on health outcomes.

The evidence for genetic testing in individuals who have AMD includes genetic association studies and risk prediction models. Relevant outcomes are test validity, change in disease status and functional outcomes. The analytic validity of genetic testing for assessing the risk of progression to advanced AMD is high. The clinical utility of genetic testing in patients who have AMD is limited, in that genetic testing has not been shown to be superior to clinical evaluation in determining the risk of progression of disease. In addition, there is no known association with specific genotypes and specific therapies. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background
Description of the Disease
Macular degeneration, the leading cause of severe vision loss in people older than age 60 years, occurs when the central portion of the retina, the macula, deteriorates. Because the disease develops as a person ages, it is often referred to as age-related macular degeneration (AMD). AMD has an estimated prevalence of 1 in 2,000 people in the United States and affects individuals of European descent more frequently than African-Americans in the United States.

There are 2 major types of AMD, known as the dry form and the wet form. The dry form is much more common, accounting for 85% to 90% of all cases of AMD, and it is characterized by the buildup of yellow deposits called drusen in the retina and slowly progressive vision loss. The condition typically affects vision in both eyes, although vision loss often occurs in 1 eye before the other. AMD is generally thought to progress along a continuum from dry AMD to neovascular wet AMD, with approximately 10% to 15% of all AMD patients eventually developing the wet form. Occasionally, patients with no prior signs of dry AMD present with wet AMD as the first manifestation of the condition.

The wet form of AMD is characterized by the growth of abnormal blood vessels from the choroid underneath the macula, and is associated with severe vision loss that can rapidly worsen. The abnormal vessels leak blood and fluid into the retina, which damages the macula, leading to permanent loss of central vision.

Major risk factors for AMD include older age, cigarette smoking, cardiovascular diseases, nutritional factors and certain genetic markers. Age appears to be the most important risk factor, as the chance of developing the condition increases significantly as a person gets older. Smoking is another established risk factor. Other factors that may increase the risk of AMD include high blood pressure, heart disease, a high-fat diet or one that is low in certain nutrients (e.g., antioxidants, zinc) and obesity.

Clinical Diagnosis of AMD
AMD can be detected by routine eye exam, with one of the most common early signs being the presence of drusen or pigment clumping. An Amsler grid, a pattern of straight lines that resemble a checkerboard, may also be used. In an individual with AMD, some of the straight lines may appear wavy or missing.

If AMD is suspected, fluorescein angiography and/or optical coherence tomography (OCT) may be performed. Angiography involves injecting a dye into the bloodstream to identify leaking blood vessels in the macula. OCT captures a cross-section image of the macula and aids in identifying fluid beneath the retina and in documenting degrees of retinal thickening.

Treatment of AMD
There is currently no cure for macular degeneration, but certain treatments may prevent severe vision loss or slow the progression of the disease. For dry AMD, there is no medical treatment; however, changing certain lifestyle risks may slow the onset and progression of AMD. The goal for wet (advanced) AMD is early detection and treatment aimed at preventing the formation of new blood vessels, or sealing the leakage of fluid from blood vessels that have already formed. Treatment options include laser photocoagulation, photodynamic therapy, surgery, anti-angiogenic drugs and combination treatments. Anti-angiogenesis drugs block the development of new blood vessels and leakage from the abnormal vessels within the eye that cause wet macular degeneration and may lead to patients regaining lost vision. A large study performed by the National Eye Institute of the National Institutes of Health, the Age-Related Eye Disease Study (AREDS), showed that for certain individuals (those with extensive drusen or neovascular AMD in 1 eye) high doses of vitamins C, E, beta-carotene and zinc may provide a modest protective effect against the progression of AMD.1 

Genetics of AMD
It has been reported that genetic variants associated with AMD account for approximately 70% of the risk for the condition.2 

More than 25 genes have been reported to influence the risk of developing AMD, discovered initially through family-based linkage studies, and subsequently through large-scale genome-wide association studies. Genes influencing several biological pathways, including genetic loci associated with the regulation of complement, lipid, angiogenic and extracellular matrix pathways, have been found to be associated with the onset, progression and bilateral involvement of early, intermediate and advanced stages of AMD.3 

Loci based on common single nucleotide polymorphisms (SNPs) contribute to the greatest AMD risk: 

  • the long (q) arm of chromosome 10 in a region known as 10q26 contains 2 genes of interest, ARMS2 and HTRA1. Changes in both genes have been studied as possible risk factors for the disease; however, because the 2 genes are so close together, it is difficult to tell which gene is associated with age-related macular degeneration risk, or whether increased risk results from variations in both genes.
  • common and rare variants in the complement factor H (CFH) gene.

Other confirmed genes in the complement pathway include C2, C3, CFB and CFI.3

On the basis of large genome-wide association studies, high-density lipoprotein cholesterol pathway genes have been implicated, including CETP and LIPC, and possibly LPL and ABCA1.3 The collagen matrix pathway genes COL10A1 and COL8A1, apolipoprotein E APOE and the extracellular matrix pathway genes TIMP3 and FBN2 have also been linked to AMD. Genes involved in DNA repair (RAD51B) and in the angiogenesis pathway (VEGFA) have also been associated with AMD. 

Commercially Available Testing for AMD
Commercially available genetic testing for AMD is aimed at identifying those individuals who are at risk of developing advanced AMD. 

Arctic Medical Laboratories offers Macula Risk®, which uses patient clinical information and the patient’s genotype for 15 associated biomarkers in an algorithm to identify Caucasians at high risk for progression of early or intermediate AMD to advanced forms of AMD. A Vita Risk® report is also provided with vitamin recommendations based on the CFH/ARMS2 genotype.

Nicox offers Sequenom’s RetnaGene AMD in North America. RetnaGene evaluates the risk of a patient with early or intermediate AMD progressing to advanced choroidal neovascular disease (wet AMD) within 2, 5 and 10 years. The RetnaGene AMD test assesses the impact of 12 genetic variants (single nucleotide polymorphisms) located on genes that are collectively associated with the risk of progressing to advanced disease in patients with early- or intermediate-stage disease (CFH/CFH region, C2, CRFB, ARMS2, C3). A risk score is generated, and the patient is categorized into one of 3 risk groups: low, moderate or high risk. 

ARUP laboratory offers testing for mutations in the ARMS2 and CFH genes. deCode Complete includes testing for mutations in CFH, ARMS2/HTRA1, C2, DFB and C3 genes. 23andMe includes testing for CFH, ARMS2 and C2. 

Regulatory Status
No U.S. Food and Drug Administration (FDA)-cleared genotyping tests were found. Thus, genotyping is offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA).

Related Policies
90324 Intravitreal Angiogenesis Inhibitors for Choroidal Vascular Conditions

Policy
Genetic testing for macular degeneration is considered INVESTIGATIONAL.

Policy Guidelines
Genetic Counseling
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

If the testing is specific to particular genes that have been codified and does not involve any risk algorithm, the test can be reported with the Tier 2 CPT code(s).

Under code 81401:
APOE (apolipoprotein E) (e.g., hyperlipoproteinemia type III, cardiovascular disease, Alzheimer's disease), common variants (e.g., *2, *3, *4)

CFH/ARMS2 (complement factor H/age-related maculopathy susceptibility 2) (e.g., macular degeneration), common variants (e.g., Y402H [CFH], A69S [ARMS2])

Under 81405:
HTRA1 (HtrA serine peptidase 1) (e.g., macular degeneration), full gene sequence

Under code 81408:
ABCA4 (ATP-binding cassette, sub-family A [ABC1], member 4) (e.g., Stargardt disease, age-related macular degeneration), full gene sequence

If the specific testing is not listed in Tier 2, the unlisted molecular pathology code 81479 would be reported. If the testing involves multiple analytes and an algorithm, the unlisted multianalyte assay with algorithmic analysis (MAAA) code 81599 would be reported. 

Benefit Application
BlueCard®/National Account Issues
No applicable information.

Rationale
Analytic Validity
Analytic validity is the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent.

According to a major laboratory’s website, the analytic sensitivity and specificity of testing for mutations in the ARMS2 gene and CFH gene by polymerase chain reaction is 99%.4 

Clinical Validity
Clinical validity is the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values) in detecting clinical disease.

How well can the test predict the risk of developing advanced age-related macular degeneration (AMD)?

Current models for predicting AMD risk include various combinations of epidemiologic, clinical and genetic factors, and give areas under the curve (AUC) of approximately 0.8.5-8 (By plotting the true and false positives of a test, an AUC measures the discriminative ability of the test, with a perfect test giving an AUC of 1.) 

A 2009 analysis by Seddon et al. demonstrated that a model of AMD risk that included age, gender, education, baseline AMD grade, smoking and body mass index had an AUC of 0.757.8 The addition of the genetic factors (SNPs) in CFH, ARMS2, C2, C3 and CFB increased the AUC to 0.821. In a 2015 report, Seddon et al. included 10 common and rare genetic variants in their risk prediction model, resulting in an AUC of 0.911 for progression to advanced AMD.9 Klein et al. showed that an individual’s macular phenotype, as represented by the Age-Related Eye Disease Study (AREDS) Simple Scale score, which rates the severity of AMD based on the presence of large drusen and pigment changes to predict the rate of advanced AMD, has the greatest predictive value.5,10 The predictive model used in this analysis by Klein included age, family history, smoking, the AREDS Simple Scale score, presence of very large drusen, presence of advanced AMD in 1 eye and genetic factors (CFH and ARMS2). The AUC was 0.865 without genetic factors included and 0.872 with genetic factors included.5 

Although these risk models suggest some small incremental increase in the ability to assess risk of developing advanced AMD based on genetic factors, the clinical utility is not established.

Clinical Utility
Clinical utility is how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes.

What can be done for an individual whose genetic test indicates that he or she is at high risk for vision loss from AMD? The possible clinical utility of genetic testing for AMD can be divided into disease prevention, disease monitoring and therapy guidance, as discussed in more detail below. 

  • Prevention: Genetic testing and risk prediction for AMD would have clinical utility if a preventive therapy existed that involved an intervention that went beyond good health practices (e.g., no smoking, balanced diet, exercise, nutrient supplements). If a preventive therapy existed, the optimal risk-benefit point along the AMD risk profile for every given age would need to be established so that the decision could be made which individuals should receive those treatments and at what age to start the intervention. Currently, no preventive measures are available; high-dose antioxidants and zinc supplements have been shown to reduce the progression of disease.1 
  • Monitoring: If a patient is identified as high risk, changes in the frequency of monitoring may occur and could include the possibility of home monitoring devices, or the use of technology such as preferential hyperacuity perimetry to detect early or subclinical wet AMD. However, the impact of more frequent monitoring for high-risk patients is not known.5 
  • Guide therapy: There have been no consistent associations between response to vitamin supplements or anti-VEGF (vascular endothelial growth factor) therapy and VEGF gene polymorphisms.11-15 

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials

NCT No. Trial Name Planneed Enrollment Completion Date

Ongoing

NCT01115387

GARM II: A Study on the Genetics of Age-related Maculopathy

7,000 

Aug 2016 

Unpublished

NCT01650948a

Evaluation of Genetic Variants in Patients Under Treatment for Choroidal Neovascular (CNV) Age-related Macular Degeneration (AMD), Receiving Intravitreal antiVEGF Injections to Evaluate the Association Between Genetic Load and Phenotypes Associated With More Aggressive Forms of Disease

100  Completed Dec 2013 

NCT:  national clinical trial.
ª Denotes industry-sponsored or cosponsored trial. 

Summary of Evidence
The evidence for genetic testing in individuals who are asymptomatic with risk of developing age-related macular degeneration (AMD) includes genetic association studies and risk prediction models. Relevant outcomes are test validity, change in disease status and functional outcomes. The analytic validity of genetic testing for AMD is high, and the clinical validity of genetic testing appears to provide a small, incremental benefit to risk stratification based on nongenetic risk factors. The clinical utility of genetic testing for AMD is limited, in that there are currently no preventive measures that can be undertaken. No studies have shown improvement in health outcomes in patients who have been identified as being at high risk based on genetic testing. The evidence is insufficient to determine the effects of the technology on health outcomes.

The evidence for genetic testing in individuals who have AMD includes genetic association studies and risk prediction models. Relevant outcomes are test validity, change in disease status and functional outcomes. The analytic validity of genetic testing for assessing the risk of progression to advanced AMD is high. The clinical utility of genetic testing in patients who have AMD is limited, in that genetic testing has not been shown to be superior to clinical evaluation in determining the risk of progression of disease. In addition, there is no known association with specific genotypes and specific therapies. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements
The 2014 American Academy of Ophthalmology (AAO) Task Force on Genetic Testing recommendations specific to genetic testing for complex eye disorders like AMD state that the presence of any one of the disease-associated variants is not highly predictive of the development of disease.16 The AAO Task Force finds that in many cases, 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. AAO concludes that genetic testing for complex diseases will become relevant to the routine practice of medicine when clinical trials demonstrate that patients with specific genotypes benefit from specific types of therapy or surveillance; until such benefit can be demonstrated, the routine genetic testing of patients with complex eye diseases, or unaffected patients with a family history of such diseases, is not warranted.

U.S. Preventive Services Task Force Recommendations
No U.S. Preventive Services Task Force recommendations for genetic testing for macular degeneration have been identified.

References

  1. Age-Related Eye Disease Study Research G. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. Oct 2001;119(10):1417-1436. PMID 11594942
  2. Gorin MB. Genetic insights into age-related macular degeneration: controversies addressing risk, causality, and therapeutics. Mol Aspects Med. Aug 2012;33(4):467-486. PMID 22561651
  3. Lim LS, Mitchell P, Seddon JM, et al. Age-related macular degeneration. Lancet. May 5 2012;379(9827):1728-1738. PMID 22559899
  4. http://ltd.aruplab.com/Tests/Pub/0051674. Accessed September 5, 2014.
  5. Kim IK. Genetic testing for AMD inches forward. 2012; http://www.revophth.com/content/d/retina/c/35327/.Accessed September 5, 2014.
  6. Hageman GS, Gehrs K, Lejnine S, et al. Clinical validation of a genetic model to estimate the risk of developing choroidal neovascular age-related macular degeneration. Hum Genomics. Jul 2011;5(5):420-440. PMID 21807600
  7. Jakobsdottir J, Gorin MB, Conley YP, et al. Interpretation of genetic association studies: markers with replicated highly significant odds ratios may be poor classifiers. PLoS Genet. Feb 2009;5(2):e1000337. PMID 19197355
  8. Seddon JM, Reynolds R, Maller J, et al. Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci. May 2009;50(5):2044-2053. PMID 19117936
  9. Seddon JM, Silver RE, Kwong M, et al. Risk Prediction for Progression of Macular Degeneration: 10 Common and Rare Genetic Variants, Demographic, Environmental, and Macular Covariates. Invest Ophthalmol Vis Sci. Apr 2015;56(4):2192-2202. PMID 25655794
  10. Klein ML, Francis PJ, Ferris FL, 3rd, et al. Risk assessment model for development of advanced age-related macular degeneration. Arch Ophthalmol. Dec 2011;129(12):1543-1550. PMID 21825180
  11. Fauser S, Lambrou GN. Genetic predictive biomarkers of anti-VEGF treatment response in patients with neovascular age-related macular degeneration. Surv Ophthalmol. Mar-Apr 2015;60(2):138-152. PMID 25596882
  12. Chew EY, Klein ML, Clemons TE, et al. No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements: AREDS report number 38. Ophthalmology. Nov 2014;121(11):2173-2180. PMID 24974817
  13. Hagstrom SA, Ying GS, Maguire MG, et al. VEGFR2 Gene Polymorphisms and Response to Anti-Vascular Endothelial Growth Factor Therapy in Age-Related Macular Degeneration. Ophthalmology. Aug 2015;122(8):1563-1568. PMID 26028346
  14. Hagstrom SA, Ying GS, Pauer GJ, et al. VEGFA and VEGFR2 gene polymorphisms and response to antivascular endothelial growth factor therapy: comparison of age-related macular degeneration treatments trials (CATT). JAMA Ophthalmol. May 2014;132(5):521-527. PMID 24652518
  15. Awh CC, Lane AM, Hawken S, et al. CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmology. Nov 2013;120(11):2317-2323. PMID 23972322
  16. American Academy of Ophthamology (AAO). Recommendations for genetic testing of inherited eye diseases. 2014; http://one.aao.org/clinical-statement/recommendations-genetic-testing-of-inherited-eye-d. Accessed October 29, 2014.

Coding Section

Codes Number Description
CPT   No specific CPT code. See Policy Guidelines
ICD-9-CM Diagnosis   Investigational for all relevant diagnoses
ICD-10-CM (effective 10/01/15)   Investigational for all relevant diagnoses
  H35.30-H35.32 Age-related macular degeneration code range
  Z13.5 Encounter for screening for eye and ear disorders
ICD-10-PCS (effective 10/01/15)   No applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.
Type of Service    
Place of Service    

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. 

Appendix
Appendix Table 1. Categories of Genetic Testing Addressed in 204103

Category Addressed

1. Testing of an affected individual’s germline to benefit the individual

 

1a. Diagnostic

 

1b. Prognostic

 

1c. Therapeutic

X

2. Testing cancer cells from an affected individual to benefit the individual

 

2a. Diagnostic

 

2b. Prognostic

 

2c. Therapeutic

 

3. Testing an asymptomatic individual to determine future risk of disease

X

4. Testing of an affected individual’s germline to benefit family members

 

5. Reproductive testing

 

5a. Carrier testing: preconception

 

5b. Carrier testing: prenatal

 

5c. In utero testing: aneuploidy

 

5d. In utero testing: mutations

 

5e. In utero testing: other

 

5f. Preimplantation testing with in vitro fertilization 

 

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 and Blue Shield Association technology assessment program (TEC) and other non-affiliated 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     

07/12/2019 

Annual review, no change to policy intent. 

07/18/2018 

Annual review, no change to policy intent. 

07/12/2017 

Annual review, no change to policy intent. 

04/25/2017 

Updated category to Laboratory. No other changes 

01/05/2017 

Annual review, no change to policy intent. 

01/26/2016 

Annual review, no change to policy intent. Updating background, description, related policies, guidelines, rationale and references. Adding appendix 1. 

01/19/2015 

Annual review, no change to policy intent. Updated description, background, related policies, rationale & references. Added coding. 

01/08/2014

NEW POLICY

 


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