Policy

BCBSNC will provide coverage for genetic testing for alpha- and beta- thalassemia when it is determined the medical criteria or reimbursement guidelines below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore, member benefit language should be reviewed before applying the terms of this medical policy. 

When Genetic Testing for Alpha- and Beta- Thalassemia is covered

Reimbursement for genetic testing to confirm an alpha- or beta-thalassemia diagnosis is allowed in any of the following situations:

1. For individuals for whom one parent is a known carrier of alpha- or beta-thalassemia.
2. For individuals for whom other testing to diagnose the cause of microcytic anemia has been inconclusive 

When Genetic Testing for Alpha- and Beta- Thalassemia is not covered

For all other situations not described above, genetic testing for alpha- or beta- thalassemia is considered investigational.

Policy Guidelines

Background

Thalassemias result from deficiencies in hemoglobin biosynthesis due to mutations in or near the two globin gene clusters which encode the globin polypeptide subunits of hemoglobin (Benz Jr & Angelucci, 2024). Normal hemoglobin is a heterotetramer of two alpha globin chains and two beta globin chains (hemoglobin A) or two gamma globin chains (hemoglobin F). Well over 100 mutations have been documented to affect the biosynthesis or post-translational stability of the globin subunits needed for successful production of the large amounts of Hb needed for normal red cell homeostasis. Globin chain synthesis is very tightly controlled, such that the ratio of production of alpha to non-alpha chains is almost exactly 1:1 (Benz Jr, 2024b).

Alpha thalassemia refers to thalassemias that result from impaired or absent production of alpha globin, leading to a relative excess of gamma globin (fetus and newborn), or excess beta globin (children and adults). Excess beta globin chains can form soluble homotetramers, but they are nonfunctional and unstable. This may lead to increased hemolysis and a variety of clinical manifestations, such as anemia, thrombosis, and skeletal changes. A diagnosis of alpha thalassemia is often confirmed by genetic testing, as assessment of the hemoglobin gene is inexpensive and convenient (Benz Jr, 2024b).

The clinical severity is directly attributable to the net deficit of alpha globin synthesis but is complicated by the number of alpha globin genes affected, which of the two alpha globin loci is affected, and the degree to which the mutation blocks gene expression. In addition, combinations of defects in both alpha and beta globulins can balance each other out. Thus, understanding the broad spectrum of clinical severity in alpha thalassemia requires a detailed knowledge of the underlying genetic defect and the impact of these defects on the overall levels and balance of globin chain synthesis (Benz Jr, 2023).

The majority of cases of alpha thalassemia are attributable to deletion of alpha globin alleles, especially in Asia and Africa (Steinberg, 1999). However, more detailed analysis of globin gene sequences suggests that some fairly common forms of alpha thalassemia that appear to arise from a deletion of one copy of an alpha globin gene are actually due to unequal crossover and recombination events that fuse the two alpha globin genes together into one (Benz Jr, 2024b). Additionally, non-deletion alleles are also common, especially in the Mediterranean area, which contain mutations producing highly unstable alpha globin variants unable to produce intact hemoglobin (Benz Jr & Angelucci, 2024). Current research continues to identify novel mutations and improve thalassemia screening (He et al., 2018).

Beta-thalassemia is similar to alpha-thalassemia, with the beta chains of hemoglobin affected instead of the alpha chains. However, excess alpha globin chains do not form soluble homotetramers, causing them to aggregate when they accumulate in erythroid precursors. This causes clinical symptoms to be more severe, although the symptoms themselves are similar to alpha-thalassemia (anemia, iron overload, and so on) (Benz Jr, 2023; Benz Jr & Angelucci, 2024). There are two beta globin genes compared to four for the alpha chain. As with alpha-thalassemia, the severity of clinical presentation depends on the genotype of the beta globin genes (i.e. the ratio of beta to alpha globin chains). Mutations may result in a reduced expression (β+) or absent expression (β0 ). β0 phenotypes are generally transfusion-dependent as they produce very little (if any) adult hemoglobin (Benz Jr, 2023).

Due to the frequency of thalassemias worldwide, carrier screening may be useful, particularly in areas such as Southeast Asia, Africa, and the Indian subcontinent. Both primary thalassemias are autosomal recessive genetic disorders so parents who are heterozygous carriers would have a 25% chance to have an affected child despite being asymptomatic themselves. Identification of an affected fetus could alter decisions during the pregnancy (Yates, 2023).

Below is a table summarizing the clinical genotypes and phenotypes of both thalassemia syndromes (Benz Jr, 2024a; Benz Jr & Angelucci, 2024; Steinberg, 2024) (figure from Benz Jr).

OMIM Online Mendelian Inheritance in Man
Values round to ≥ 0.02 (two decimal places).

Table 5. Genes that were ascertained for screening outside of the gnomAD criteria.

ACMG American College of Medical Genetics and Genomics, ACOG American College of Obstetricians and Gynecologists, AJ Ashkenazi Jewish (≥ 2% of the US population), OMIM Online Mendelian Inheritance in Man, ^55 PR Puerto Rican, SEA South East Asian.
Carrier frequency of a sequence variant is < 1/200, if reported in gnomAD^50.
Diagnostic laboratory data was not used for carrier frequency data.
Specific data for general US population not available; however, recognized as common among many US immigrant populations. ^62
This term is no longer used by the journal but is used in the original article to which these studies refer. We have therefore not changed the term but recognize it does not accurately describe the ancestry of the populations originally studied.^46

(Gregg et al., 2021)

Canadian College of Medical Geneticists (CCMG) and Society of Obstetricians and Gynaecologists of Canada (SOGC)

The CCMG and SOGC published a joint guideline titled “Carrier Screening for Thalassemia and Hemoglobinopathies in Canada” in 2008. Their recommendations addressing thalassemia’s/hemoglobinopathies are listed below:

1. “Carrier screening for thalassemia and hemoglobinopathies should be offered to a woman if she and/or her partner are identified as belonging to an ethnic population whose members are at higher risk of being carriers. Ideally, this screening should be done pre-conceptionally or as early as possible in the pregnancy. (II-2A) 
2. Screening should consist of a complete blood count, as well as hemoglobin electrophoresis or hemoglobin high performance liquid chromatography. This investigation should include quantitation of HbA2 and HbF. In addition, if there is microcytosis (mean cellular volume < 80 fL) and/or hypochromia (mean cellular hemoglobin < 27 pg) in the presence of a normal hemoglobin electrophoresis or high-performance liquid chromatography the patient should be investigated with a brilliant cresyl blue stained blood smear to identify H bodies. A serum ferritin (to exclude iron deficiency anemia) should be performed simultaneously. (III-A)
3. If a woman’s initial screening is abnormal (e.g., showing microcytosis or hypochromia with or without an elevated HbA2, or a variant Hb on electrophoresis or high-performance liquid chromatography) then screening of the partner should be performed. This would include a complete blood count as well as hemoglobin electrophoresis or HPLC, HbA2 and HbF quantitation, and H body staining. (III-A) 
4. If both partners are found to be carriers of thalassemia or an Hb variant, or of a combination of thalassemia and a hemoglobin variant, they should be referred for genetic counselling. Ideally, this should be prior to conception, or as early as possible in the pregnancy. Additional molecular studies may be required to clarify the carrier status of the parents and thus the risk to the fetus. (II-3A)
5. Prenatal diagnosis should be offered to the pregnant woman/couple at risk for having a fetus affected with a clinically significant thalassemia or hemoglobinopathy. Prenatal diagnosis should be performed with the patient’s informed consent. If prenatal diagnosis is declined, testing of the child should be done to allow early diagnosis and referral to a pediatric hematology centre, if indicated. (II-3A)
6. Prenatal diagnosis by DNA analysis can be performed using cells obtained by chorionic villus sampling or amniocentesis. Alternatively, for those who decline invasive testing and are at risk of hemoglobin Bart’s hydrops fetalis (four-gene deletion α-thalassemia), serial detailed fetal ultrasound for assessment of the fetal cardiothoracic ratio (normal < 0.5) should be done in a centre that has experience conducting these assessments for early identification of an affected fetus. If an abnormality is detected, a referral to a tertiary care centre is recommended for further assessment and counselling. Confirmatory studies by DNA analysis of amniocytes should be done if a termination of pregnancy is being considered. (II-3A) 
7. The finding of hydrops fetalis on ultrasound in the second or third trimester in [individuals] with an ethnic background that has an increased risk of α-thalassemia should prompt immediate investigation of the pregnant patient and her partner to determine their carrier status for α-thalassemia. (III-A)” (Langlois et al., 2008).

The Thalassemia Longitudinal Cohort

The report on the Thalassemia Longitudinal Cohort recommends: “Obtaining genotyping to confirm the diagnosis and HLA typing for transplant evaluation for all patients who require chronic transfusion is strongly recommended. For pediatric patients, annual comprehensive follow up should include assessment of the availability of a related donor as well as a recommendation to bank cord blood and obtain HLA typing on all subsequently born full siblings” (Tubman et al., 2015).

American College of Obstetrics and Gynecology (ACOG)

The ACOG Committee Opinion #691 (“Carrier Screening for Genetic Conditions”) states that: “Couples at risk of having a child with a hemoglobinopathy may benefit from genetic counseling to review their risk, the natural history of these disorders, prospects for treatment and cure, availability of prenatal genetic testing, and reproductive options. Prenatal diagnostic testing for the mutation responsible for sickle cell disease is widely available. Testing for α-thalassemia and β-thalassemia is possible if the mutations and deletions have been previously identified in both parents. These DNA-based tests can be performed using chorionic villi obtained by chorionic villus sampling or using cultured amniotic fluid cells obtained by amniocentesis. For some couples, preimplantation genetic diagnosis in combination with in vitro fertilization may be a desirable alternative to avoid termination of an affected pregnancy. Preimplantation genetic diagnosis has been successfully performed for sickle cell disease and most types of β-thalassemia” (ACOG, 2017). This was reaffirmed in 2020.

In 2022, ACOG put out a new practice bulletin regarding hemoglobinopathies in pregnancy (originally published in 2007) and reaffirmed this in 2023 with a few additions (ACOG, 2022).

• ACOG “recommends offering universal hemoglobinopathy testing to persons planning pregnancy or at the initial prenatal visit if no prior testing results are available for interpretation.”
• “Hemoglobinopathy testing may be performed using hemoglobin electrophoresis or molecular genetic testing (eg, expanded carrier screening that includes sickle cell disease [SCD] and other hemoglobinopathies).”
• “The use of noninvasive prenatal diagnosis for SCD with cell-free fetal DNA is still experimental and currently not recommended” (ACOG, 2022). 

National Health Service (NHS)

The NHS released standards for antenatal laboratories working with the NHS sickle cell and thalassaemia (SCT) screening program (NHS, 2021). The referral guidelines for antenatal screening specimens are as follows:

a thalassaemia (MCH < 25pg)

The Association of Public Health Laboratories (APHL)

The Association of Public Health Laboratories (APHL) states that “Molecular testing can be added to resolve cases when the newborn has been transfused with packed red blood cells. Since the newborn’s phenotype is masked by the donor, DNA testing can be used to identify any abnormal hemoglobins” (APHL, 2015). 

Public Health England (PHE)

The PHE highlights the importance of antenatal screening. If the baby’s mother is identified as a carrier, the biological father should also be tested. Both prenatal diagnosis and genetic counselling are recommended by the PHE (PHE, 2022).

British Society for Haematology (BSH)

The BSH provides the following recommendations:

• “Antenatal screening/testing of pregnant [individuals] should be carried out according to the guidelines of the NHS Sickle Cell and Thalassaemia Screening programme.
• Laboratories performing antenatal screening should utilize methods capable of detecting significant variants and be capable of quantitating haemoglobins A 2 and F at the cut‐off points required by the national antenatal screening program” (Ryan et al., 2010).

Genetic counseling is also permitted for prospective parents.

The Thalassemia International Foundation (TIF)

The TIF provided recommendations for the management of transfusion dependent Thalassemia. The following recommendations were made (TIF, 2021):

• “Molecular genetic testing is available in clinical laboratories and may be useful for predicting the clinical phenotype in some cases as well as enabling presymptomatic diagnosis of at-risk family members and prenatal diagnosis.
• Molecular analysis is not required to confirm the diagnosis of a β carrier, but it is necessary to confirm the α thalassemia carrier status (grade A) 
• Since the prevalent pathogenic variants of the β globin gene are limited in each at-risk population, a PCR method designed to detect the common specific mutation simultaneously should be used initially (grade B)
• β globin gene sequence analysis may be considered first if the affected individual is not of an ancestry at high risk or if targeted analysis reveals only one or no pathogenic variant (grade B)
• α thalassemias are mainly due to deletions of different length and they can be detected preferentially by reverse dot blot and Gap-PCR (grade B) 
• Methods that may be used to detect rare or unknown deletions include: Southern blotting (now fallen into abeyance), quantitative PCR, long-range PCR and, above all, MLPA (grade B)” (TIF, 2021). 

State and Federal Regulations, as applicable

Food and Drug Administration (FDA)

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 and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). LDTs are not approved or cleared by the U. S. Food and Drug Administration; however, FDA clearance or approval is not currently required for clinical use.

Billing/Coding/Physician Documentation Information 

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 81257, 81258, 81259, 81269, 81361, 81362, 81363, 81364, S3845, S3846

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included. 

Scientific Background and Reference Sources

ACOG. (2007). ACOG Practice Bulletin No. 78: hemoglobinopathies in pregnancy. Obstet Gynecol, 109(1), 229-237. https://doi.org/10.1097/00006250-200701000-00055

ACOG. (2017). ACOG Committee Opinion 691: Carrier Screening for Genetic Conditions. Obstet Gynecol, 129, e41-e55. https://doi.org/10.1097/AOG.0000000000001952

ACOG. (2018). ACOG Publications. Obstetrics & Gynecology, 131(1). https://journals.lww.com/greenjournal/Fulltext/2018/01000/ACOG_Publications.31.aspx

ACOG. (2022). Hemoglobinopathies in Pregnancy. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2022/08/hemoglobinopathies-in-pregnancy

APHL. (2015). Hemoglobinopathies: Current Practices for Screening, Confirmation and Follow-up. Association of Public Health Laboratories Retrieved from https://www.cdc.gov/ncbddd/sicklecell/documents/nbs_hemoglobinopathy-testing_122015.pdf

Benz Jr, E. J. (2023). Pathophysiology of thalassemia. https://www.uptodate.com/contents/pathophysiology-of-thalassemia

Benz Jr, E. J. (2024a). Classical thalassemia syndromes (genotypes and laboratory findings). In UpToDate. Waltham. MA.

Benz Jr, E. J. (2024b). Molecular pathology of the thalassemic syndromes. https://www.uptodate.com/contents/molecular-genetics-of-the-thalassemia-syndromes \

Benz Jr, E. J., & Angelucci, E. (2024, April 5). Clinical manifestations and diagnosis of the thalassemias. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-the-thalassemias

Chen, D., Shen, X., Wu, C., Xu, Y., Ding, C., Zhang, G., Xu, Y., & Zhou, C. (2020). Eleven healthy live births: a result of simultaneous preimplantation genetic testing of α- and β-double thalassemia and aneuploidy screening. Journal of assisted reproduction and genetics, 37(3), 549-557. https://doi.org/10.1007/s10815-020-01732-7

Chen, D., Shen, X., Xu, Y., Ding, C., Ye, Q., Zhong, Y., Xu, Y., & Zhou, C. (2021). Successful four-factor preimplantation genetic testing: α- and β-thalassemia, human leukocyte antigen typing, and aneuploidy screening. Systems Biology in Reproductive Medicine, 67(2), 151-159. https://doi.org/10.1080/19396368.2020.1832158

Dan, M., Gutu, B.-I., Severin, E., & Tanase, V.-G. (2023). Innovative and Needs-led research on β-thalassemia treatment methods. Frontiers in Hematology, 1. https://doi.org/10.3389/frhem.2022.1085952

Fu, Y., Shen, X., Chen, D., Wang, Z., & Zhou, C. (2019). Multiple displacement amplification as the first step can increase the diagnostic efficiency of preimplantation genetic testing for monogenic disease for β-thalassemia. J Obstet Gynaecol Res, 45(8), 1515-1521. https://doi.org/10.1111/jog.14003

Gregg, A. R., Aarabi, M., Klugman, S., Leach, N. T., Bashford, M. T., Goldwaser, T., Chen, E., Sparks, T. N., Reddi, H. V., Rajkovic, A., & Dungan, J. S. (2021). Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med, 23(10), 1793-1806. https://doi.org/10.1038/s41436-021-01203-z

He, J., Song, W., Yang, J., Lu, S., Yuan, Y., Guo, J., Zhang, J., Ye, K., Yang, F., Long, F., Peng, Z., Yu, H., Cheng, L., & Zhu, B. (2017). Next-generation sequencing improves thalassemia carrier screening among premarital adults in a high prevalence population: the Dai nationality, China. Genet Med, 19(9), 1022-1031. https://doi.org/10.1038/gim.2016.218 

He, S., Li, J., Li, D. M., Yi, S., Lu, X., Luo, Y., Liang, Y., Feng, C., Chen, B., Zheng, C., & Qiu, X. (2018). Molecular characterization of alpha- and beta-thalassemia in the Yulin region of Southern China. Gene, 655, 61-64. https://doi.org/10.1016/j.gene.2018.02.058

Langlois, S., Ford, J. C., Chitayat, D., Chitayat, D., Désilets, V. A., Farrell, S. A., Geraghty, M., Langlois, S., Nelson, T., Nikkel, S. M., Shugar, A., Skidmore, D., Allen, V. M., Audibert, F., Blight, C., Désilets, V. A., Gagnon, A., Johnson, J.-A., Langlois, S., . . . Wyatt, P. (2008). Carrier Screening for Thalassemia and Hemoglobinopathies in Canada. Journal of Obstetrics and Gynaecology Canada, 30(10), 950-959. https://doi.org/10.1016/s1701-2163(16)32975-9

Martin, A., & Thompson, A. A. (2013). Thalassemias. Pediatr Clin North Am, 60(6), 1383-1391. https://doi.org/10.1016/j.pcl.2013.08.008

NHS. (2021). SCT Screening: handbook for antenatal laboratories. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1 039978/Referral_guidelines_for_antenatal_screening_specimens_final.pdf

Nosheen, A., Ahmad, H., Qayum, I., Siddiqui, N., Abbasi, F. M., & Iqbal, M. S. (2015). Premarital genetic screening for beta thalassemia carrier status of indexed families using HbA2 electrophoresis. J Pak Med Assoc, 65(10), 1047-1049.

PHE. (2022). Sickle cell and thalassaemia screening: commission and provide. https://www.gov.uk/government/collections/sickle-cell-and-thalassaemia-screening-commission-and-provide

Ryan, K., Bain, B. J., Worthington, D., James, J., Plews, D., Mason, A., Roper, D., Rees, D. C., de la Salle, B., & Streetly, A. (2010). Significant haemoglobinopathies: guidelines for screening and diagnosis. Br J Haematol, 149(1), 35-49. https://doi.org/10.1111/j.1365-2141.2009.08054.x

Satirapod, C., Sukprasert, M., Panthan, B., Charoenyingwattana, A., Chitayanan, P., Chantratita, W., Choktanasiri, W., Trachoo, O., & Hongeng, S. (2019). Clinical utility of combined preimplantation genetic testing methods in couples at risk of passing on beta thalassemia/hemoglobin E disease: A retrospective review from a single center. PLoS One, 14(11), e0225457. https://doi.org/10.1371/journal.pone.0225457

Shook, L. M., Haygood, D., & Quinn, C. T. (2020). Clinical Utility of Confirmatory Genetic Testing to Differentiate Sickle Cell Trait from Sickle-beta(+)-Thalassemia by Newborn Screening. Int J Neonatal Screen, 6(1). https://doi.org/10.3390/ijns6010007

Steinberg, M. H. (1999). Management of sickle cell disease. N Engl J Med, 340(13), 1021-1030. https://www.nejm.org/doi/10.1056/NEJM199904013401307

Steinberg, M. H. (2024). Structure and function of normal hemoglobins. https://www.uptodate.com/contents/structure-and-function-of-normal-hemoglobins

TIF. (2021). 2021 GUIDELINES FOR THE MANAGEMENT OF TRANSFUSION DEPENDENT THALASSAEMIA (TDT). https://www.thalassemia.org/boduw/wp-content/uploads/2021/06/TIF-2021-Guidelines-for-Mgmt-of-TDT.pdf

Tubman, V. N., Fung, E. B., Vogiatzi, M., Thompson, A. A., Rogers, Z. R., Neufeld, E. J., & Kwiatkowski, J. L. (2015). Guidelines for the Standard Monitoring of Patients with Thalassemia: Report of the Thalassemia Longitudinal Cohort. J Pediatr Hematol Oncol, 37(3), e162-169. https://doi.org/10.1097/mph.0000000000000307

Yates, A. (2023). Prenatal screening and testing for hemoglobinopathy. https://www.uptodate.com/contents/prenatal-screening-and-testing-for-hemoglobinopathy

Zhang, H., Li, C., Li, J., Hou, S., Chen, D., Yan, H., Chen, S., Liu, S., Yin, Z., Yang, X., Tan, J., Huang, X., Zhang, L., Fang, J., Zhang, C., Li, W., Guo, J., & Lei, D. (2019). Next-generation sequencing improves molecular epidemiological characterization of thalassemia in Chenzhou Region, P.R. China. Journal of clinical laboratory analysis, 33(4), e22845-e22845. https://doi.org/10.1002/jcla.22845

Specialty Matched Consultant Advisory Panel review 7/2019

Medical Director review 7/2019

Specialty Matched Consultant Advisory Panel review 7/2020 

Medical Director review 7/2020

Specialty Matched Consultant Advisory Panel review 7/2021

Medical Director review 7/2021

Medical Director review 7/2022

Medical Director review 7/2023

Medical Director review 7/2024

Policy Implementation/Update Information

For policy titled: Genetic Testing for Alpha Thalassemia

1/1/2019 BCBSNC will provide coverage for genetic testing for alpha thalassemia when it is determined to be medically necessary because the criteria and guidelines are met. Medical Director review 1/1/2019. (jd)

8/13/2019 Specialty Matched Consultant Advisory Panel review 7/2019. Medical Director review 7/2019. (jd)

For policy titled: Genetic Testing for Alpha- and Beta- Thalassemia:

9/10/2019 Reviewed by Avalon 2nd Quarter 2019 CAB with title change. Added characteristics of beta-thalassemia and Related Policies to the Description section. Indications for beta-thalassemia added to the policy statement along with both the When Covered and When Not Covered sections. Policy guidelines updated. Added the following codes to the Billing/Coding section: S3845, S3846, and removed code table. References updated. Medical Director review 8/2019. (jd)

10/29/19 Wording in the Policy, When Covered, and/or Not Covered section(s) changed from Medical Necessity to Reimbursement language, where needed. (hb)

7/28/20 Reviewed by Avalon 2nd Quarter 2020 CAB. Added item 1 reimbursement language for genetic counseling and revised item 3 from medically necessary to reimbursement language under the When Covered section. Policy guidelines and references updated. Added the following codes to the Billing/Coding section: 81361, 81362, 81363, 81364, 96040, S0265. Specialty Matched Consultant Advisory Panel review 7/2020. Medical Director review 7/2020. (jd)

8/24/21 Reviewed by Avalon 2nd Quarter 2021 CAB. Description, Policy guidelines, and Reference sections update. Specialty Matched Consultant Advisory Panel review 7/2021. Medical Director review 7/2021. (jd)

9/13/22 Reviewed by Avalon 2nd Quarter 2022 CAB. Description, Policy guidelines, and Reference sections updated. No change to policy statement. Medical Director review 7/2022. (tm)

8/15/23 Reviewed by Avalon 2nd Quarter 2023 CAB. Updated the background, guidelines and recommendations, and evidence-based scientific references. Genetic counseling recommendation moved from When Covered to the Policy Description. Medical Director review 7/2023. (rp) 

9/4/24 Reviewed by Avalon 2nd Quarter 2024 CAB. Updated Description, Policy Guidelines, and References. No change to policy statement. Medical Director review 7/2024. (tm)