| Coverage Policy Manual | |
| Policy #: | 2012068 |
| Category: | Laboratory |
| Initiated: | November 2012 |
| Last Review: | September 2023 |
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| Genetic Test: Preconception or Prenatal Testing as a Carrier Screen | |
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| Description: |
The goal of carrier screening is to detect serious diseases in at-risk couples. Carrier screening is performed to identify individuals at risk of having offspring with inherited recessive single-gene disorders. Carriers are usually not at risk of developing the disease but can pass pathogenic variants to their offspring. Carrier testing may be performed in the prenatal or preconception periods.
Inherited Recessive Disorders
There are more than 1300 inherited recessive disorders (autosomal or X-linked) that affect 30 out of every 10,000 children (Henneman, 2016). Some diseases have limited impact on either length or quality of life, while others are uniformly fatal in childhood.
Targeted Carrier Screening
Carrier screening tests asymptomatic individuals in order to identify those who are heterozygous for serious or lethal single-gene disorders. The purpose of screening is to determine the risk of conceiving an affected child and "to optimize pregnancy outcomes based on personal preferences and values (Edwards, 2015). Risk-based carrier screening is performed in individuals having an increased risk based on population carrier prevalence, or personal or family history. Conditions selected for screening can be based on ethnicities at high-risk or may be panethnic. An example of effective ethnicity-based screening involves Tay-Sachs disease, with a 90% reduction in the disease following the introduction of carrier screening in the 1970s in the U.S. and Canada (Kaback, 2000). An example of panethnic screening involves cystic fibrosis when the American College of Obstetricians and Gynecologists (ACOG) noted that ethnic intermarriage was increasing in the U.S. and recommended panethnic cystic fibrosis carrier screening in 2005 (Banda 2015; Grant, 2002; ACOG, 2005).
Non-targeted Carrier Screening
Non-targeted carrier screening involves screening individuals or couples for disorders in many genes (up to 100s) by next-generation sequencing. Non-targeted carrier screening panels may screen for diseases that are present with increased frequency in specific populations but also include a wide range of diseases for which the patient is not at increased risk of being a carrier. Arguments for non-targeted carrier screening include the potential to assess ethnicity, identify more potential conditions, efficiency, and cost. The conditions included in non-targeted carrier screening panels are not standardized and the panels may include many conditions not routinely evaluated and for which there are no existing professional guidelines.
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
A number of commercially available genetic tests exist for carrier screening. They range from testing for individual diseases to small panels designed to address testing based on ethnicity as recommended by practice guidelines (ACOG, ACMG ), to large non-targeted panels that test for numerous diseases.
Myriad's Foresight Carrier Screen provides preconception/prenatal screening in men and women for more than 175 conditions that could be passed on to a child, providing information for pregnancy planning and management. Testing is performed using full-exon sequencing and panel-wide deletion calling.
Progenity offers prenatal carrier screening tests. The Progenity Standard Panel tests for carrier status of 29 hereditary disorders. The Progenity Global Panel tests for carrier status of 200+ hereditary disorders that typically affect health in infancy or childhood.
The Horizon Carrier Screen tests for up to 274 autosomal-recessive and X-linked genetic conditions.
Coding
There is no specific code for this test. The following codes may be used to bill for this test: 81400, 81401, 81402, 81403, 81404, 81405, 81406, 81407, 81408 81200, 81209, 81220, 81221, 81222, 81223, 81241, 81242, 81243, 81244, 81250, 81251, 81252, 81253, 81255, 81256, 81257, 81260, 81290, 81291, 81332, 81330, 81479
Related policies:
2012049 Genetic Test: Prenatal Analysis of Fetal DNA in Maternal Blood to Detect Fetal Aneuploidy
2015009
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Policy/ Coverage: |
Effective August 2022
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Preconception or prenatal testing for carrier screening using the Counsyl Foresight™ Carrier Screen, the Progenity Preparent Carrier Screen or any other carrier screening panels or screening tests for which there is not an established policy of coverage does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, preconception or prenatal testing for carrier screening using the Counsyl Foresight™ Carrier Screen, the Progenity Preparent Carrier Screen or any other carrier screening panels or screening tests for which there is not an established policy of coverage is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective August 2018 through July 2022
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Preconception or prenatal testing for carrier screening using the Counsyl Foresight™ Carrier Screen, the Progenity Preparent Carrier Screen or any other carrier screening panel test does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, preconception or prenatal testing for carrier screening using the Counsyl Foresight™ Carrier Screen, the Progenity Preparent Carrier Screen or any other carrier screening panel test is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective December 2017 - July 2018
Universal Genetic Testing (Counsyl) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without primary coverage criteria, Universal Genetic Test (Counsyl) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
The Universal Genetic Test marketed by Counsyl, Redwood City, CA, uses targeted DNA mutation analysis to simultaneously test an individual or couple for over 100 genetic disorders. Couples may learn their probability of conceiving an affected child while individuals may discover if they are carriers. Counsyl is marketing this test to consumers directly through the Internet as well as through medical centers in the U.S.
According to the Food and Drug Administration (FDA), which regulates the manufacturers of genetic tests, and the Centers for Disease Control and Prevention (CDC), which promotes health and quality of life. some genetic tests offered directly to consumers lack scientific validity, while the results of other genetic tests are only meaningful in the context of a full medical evaluation,
American College of Medical Genetics (ACMG) published a “Statement on Direct-to-Consumer (DTC) Genetic Testing” (2008) which lists points on what they consider the “minimum requirement for any genetic testing protocol.” With the Universal genetic test, there is an enhanced need for genetic consultation for persons to have full informed consent prior to testing as well as post-test genetic consultation for persons who are found to be carriers for each of the diseases tested.
Even though more than 100 genetic disorders are included in the Universal Genetic Test, some key components are omitted unless specifically ordered by the physician. For example, the Fragile X syndrome which is known to be the most common form of inherited mental retardation (Knight,1996), is not included as carrier testing.
Srinivasan and colleagues (2010) published information on the Counsyl Universal Genetic Test stating that Mendelian disorders are individually rare but collectively common, forming a 'long tail' of genetic disease. The Universal Genetic Test is a non-invasive, saliva-based assay for more than 100 Mendelian diseases across all major population groups. According to the authors the test “has been exhaustively validated with a median of 147 positive and 525 negative samples per variant, demonstrating a multiplex assay whose performance compares favorably with the previous standard of care, namely blood-based single-gene carrier tests”. Because the assay is inexpensive and requires only a saliva sample, it is now increasingly feasible to make carrier testing a routine part of preconception care.
In 2012 Lazarin and colleagues (Dept of Genetics, Counsyl) reported on recent developments in genomics that they believe have led to expanded carrier screening panels capable of assessing hundreds of causal mutations for genetic disease. This new technology allows simultaneous measurement of carrier frequencies for many diseases. As the resultant rank-ordering of carrier frequencies impacts the design and prioritization of screening programs, the accuracy of this ranking is a public health concern.
A total of 23,453 individuals from many obstetric, genetics, and infertility clinics were referred for routine recessive disease carrier screening. Multiplex carrier screening was performed and results were aggregated for this study. Twenty-four percent of individuals were identified as carriers for at least one of 108 disorders, and 5.2% were carriers for multiple disorders. The study also provided information on the clinical considerations associated with routine use of expanded panels and provides support for a pan-ethnic screening paradigm that minimizes the use of "racial" categories by the physician.
Hayes Review:
The Counsyl Universal Carrier Test reportedly tests for carrier status for more than 100 Mendelian disorders. Using a multiple molecular inversion probe assay, 925 probes for the most common variants in different ethnic groups are tested. The single validation study used a combination of 131 commercial reference samples along with 454 synthetic patient specimens for variants with no commercial reference source. Each reference sample was tested ≥ 3 times with a total of 284,485 genotypes tested in the validation. This was achieved by creating “pools” of controls; that is, different controls were combined into single samples for testing. For each variant, there was a median of 147 positive and 525 negative samples tested. The authors reported a sensitivity of > 99.9% and specificity of > 99.5%, with a false-positive rate of < 0.4% and false-negative rate of 0.002%. Although this validation appears robust, there are some concerns.
None of the specimens tested in the validation were actual patient specimens collected in the same way as they are collected for the clinical test, which uses DNA extracted from a saliva specimen. Therefore, it is impossible to know if the test will perform as well with actual patient specimens. Secondly, it is not clear what the effect of using control pools in the validation was and whether individual specimens would perform in the same way. Finally, there is no independent validation of the assay on another dataset to show that the results can be replicated. Until these weaknesses are addressed, the analytical validity of this assay cannot be adequately assessed.
There are a number of ethical issues associated with the assay, the principal one of which is informed consent. It is not clear how potential patients would be counseled to ensure that they understand the risks, benefits, and limitations of carrier testing for > 100 different disorders. Without such counseling, true informed consent is not possible. In addition, there is no indication of how abnormal results would be communicated to patients and whether counseling would be available for such patients. Furthermore, although the Counsyl test includes variants for > 100 Mendelian disorders, there are some notable exclusions. For example, testing for alpha-thalassemia is not included and there is limited screening for beta-thalassemia. Since these are common disorders in certain ethnic groups (alpha-thalassemia in Southeast Asians, among others; and beta-thalassemia in individuals of Mediterranean origin, among others), further testing would be necessary in these ethnic groups. Finally, the Counsyl website claims that the genetic disorders screened are “preventable,” but does not clarify that the primary means of prevention would be termination of affected pregnancies, a solution that is unlikely to be acceptable to all potential patients.
There is insufficient published evidence to perform a Genetic Test Evaluation (GTE) health technology assessment of the Counsyl Universal Genetic test; therefore, it cannot be recommended for adoption or use at this time. The main evidence deficiencies for the Counsyl test are insufficient data on analytical validity, clinical validity, and clinical utility.
The Universal genetic test has not been reviewed by the FDA.
2014 Update
A literature search conducted using the MEDLINE database through October 2014 did not reveal any new information that would prompt a change in the coverage statement.
2015 Update
A literature search conducted through October 2015 did not reveal any new information that would prompt a change in the coverage statement.
2016 Update
A literature search conducted through October 2016 did not reveal any new information that would prompt a change in the coverage statement.
2017 Update
This policy was originally developed to address the Universal Gene Test offered by Counsyl. The test is now marketed as the Foresight™ Carrier Screen. The policy is updated to include the new test name and methodology.
A literature search conducted through October 2017 did not reveal any new literature that would prompt a change in the coverage status. There were no published studies identified using the Counsyl Foresight Carrier Screen. There is a lack of evidence on the clinical validity and clinical utility of this testing and therefore does not meet member benefit certificate primary coverage criteria.
2019 Update
A literature search was conducted through August 2019. There was no new information identified that would prompt a change in the coverage statement.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2020. No new literature was identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2021. No new literature was identified that would prompt a change in the coverage statement.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2022. No new literature was identified that would prompt a change in the coverage statement.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
A 2023 systematic review that included studies of both targeted and non-targeted carrier screening found that carriers of conditions classified as having a more severe impact were more likely to terminate pregnancy or opt for in vitro fertilization with preimplantation genetic testing (Wang, 2023).
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| References: |
ACMG Statement on Direct-to-Consumer Genetic Testing. Accessed at www.acmg.net. Last
accessed 11/21/2012. American College of Obstetricians and Gynecologists (ACOG) Committee on Genetics.(1996) Fragile X syndrome. ACOG committee opinion. Int J Gynaecol Obstet. 1996;52(2):209-210. Banda Y, Kvale MN, Hoffmann TJ, et al.(2015) Characterizing Race/Ethnicity and Genetic Ancestry for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort. Genetics. Aug 2015; 200(4): 1285-95. PMID 26092716 Chakrabarti L, Davies KE.(1997) Fragile X syndrome. Curr Opin Neurol. 1997;10(2):142-147. Committee on Genetics, American College of Obstetricians and Gynecologists.(2005) ACOG Committee Opinion. Number 325, December 2005. Update on carrier screening for cystic fibrosis. Obstet Gynecol. Dec 2005; 106(6): 1465-8. PMID 16319281 Counsyl.(2017) Simple screening for inherited health conditions. Available at https://www.counsyl.com. Last accessed November 28, 2017. Edwards JG, Feldman G, Goldberg J, et al.(2015) Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. Obstet Gynecol. Mar 2015; 125(3): 653-662. PMID 25730230 Grant MD, Lauderdale DS.(2002) Cohort effects in a genetically determined trait: eye colour among US whites. Ann Hum Biol. 2002; 29(6): 657-66. PMID 12573082 HAYES, Inc.(2012) Counsyl Universal Genetic Test. September 2012 Henneman L, Borry P, Chokoshvili D, et al.(2016) Responsible implementation of expanded carrier screening. Eur J Hum Genet. Jun 2016; 24(6): e1-e12. PMID 26980105 Kaback MM.(2000) Population-based genetic screening for reproductive counseling: the Tay-Sachs disease model. Eur J Pediatr. Dec 2000; 159 Suppl 3: S192-5. PMID 11216898 Knight SJL, Ritchie RJ, Chakrabarti L, et al.(1996) A Study of FRAXE in Mentally Retarded Individuals Referred for Fragile X Syndrome (FRAXA) Testing in the United Kingdom. Am. J. Hum. Genet. 58:906-913, 1996. Lazarin GA, Haque IS, Nazareth S, et al.(2012) An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. Genet Med. 2012 Sep 13. doi: 10.1038/gim.2012.114. Srinivasan BS, Evans EA, Flannick J, et al.(2010) A universal carrier test for the long tail of Mendelian disease. Reprod Biomed Online. 2010 Oct;21(4):537-51. |
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Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2024 American Medical Association. |
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