BlueCross and BlueShield of Montana Medical Policy/Codes
Genetic Testing for Alpha Thalassemia
Chapter: Genetic Testing
Current Effective Date: March 15, 2014
Original Effective Date: March 15, 2014
Publish Date: January 15, 2014

Alpha thalassemia represents a group of clinical syndromes characterized by hemolytic anemia of varying severity. Genetic defects in any or all of four alpha globin genes are causative of these syndromes. The diagnosis of alpha thalassemia is made by biochemical testing and microscopic analysis of the peripheral blood smear. Biochemical testing to determine whether alpha thalassemia is present should be the first step in evaluating the presence of the condition. Biochemical testing consists of complete blood count, microscopic examination of the peripheral smear, and Hgb electrophoresis. Genetic testing can elucidate the precise number and type of genetic mutations in a patient with a clinical diagnosis of alpha thalassemia.


Hemoglobin, which is the major oxygen carrying protein molecule of red blood cells, consists of two alpha globin chains and two beta globin chains. Alpha-thalassemia refers to a group of syndromes that arise from deficient production of alpha globin chains. Deficient alpha globin production leads to an excess of beta globin chains, which results in anemia by a number of mechanisms (1):

  • Ineffective erythropoiesis in the bone marrow;
  • Production of nonfunctional hemoglobin molecules;
  • Shortened survival of red blood cells due to intravascular hemolysis and increased uptake of the abnormal red blood cells (RBCs) by the liver and spleen.

The physiologic basis of alpha thalassemia is a genetic defect in the genes coding for alpha globin production. Each individual carries four genes that code for alpha globin, with the wild genotype (normal) being aa/aa. Genetic mutations may occur in any or all of these four alpha globin genes. The number of genetic mutations determines the phenotype and severity of the alpha thalassemia syndromes. The different syndromes are classified as follows:

  • Silent carrier (alpha-thalassemia minima). This arises from one of four abnormal alpha genes (aa/a-), and is a silent carrier state. A small amount of abnormal hemoglobin can be detected in the peripheral blood, and there may be mild hypochromia and microcytosis present, but there is no anemia or other clinical manifestations.
  • Thalassemia trait (alpha-thalassemia minor). This is also called alpha-thalassemia trait, and arises from the loss of two alpha globin genes, resulting on one of two genotypes (aa/--, or a-/a-). There is a mild anemia present, and red blood cells are hypochromic and microcytic. Clinical symptoms are usually absent and the disorder is detected by Hgb electrophoresis and microscopic examination of peripheral RBCs.
  • Hemoglobin H disease (HgH, alpha-thalassemia intermedia). This syndrome results from three abnormal alpha globin genes (a-/--), resulting in a moderate to severe anemia. This condition has marked phenotypic variability, but the majority of individuals have mild disease and live a normal life without medical intervention. (2)

A minority of individuals may develop clinical symptoms of chronic hemolytic anemia. These include neonatal jaundice, hepatosplenomegaly, hyperbilirubinemia, leg ulcers, and premature development of biliary tract disease. Splenomegaly can lead to the need for splenectomy, and transfusion support may be required by the third to fourth decade of life. It has been estimated that approximately 25% of patients with HgH disease will require transfusion support during their lifetime. (3) In addition, increased iron deposition can lead to premature damage to the liver and heart.

  • Hemoglobin Bart syndrome (alpha thalassemia major). This syndrome results from mutations in all four alpha globin genes (--/--), resulting in absent production of alpha globin chains. This condition causes hydrops fetalis, which often leads to intrauterine death, or death shortly after birth. There are also increased complications of pregnancy for a woman carrying a fetus with hydrops fetalis. These include hypertension, preeclampsia, antepartum hemorrhage, renal failure, premature labor, and abruption placenta.(3)

Alpha thalassemia is a common genetic disorder, affecting approximately 5% of the world’s population.(3) The frequency of mutations is highly dependent upon ethnicity, with the highest rates seen in Asians, and much lower rates in Northern Europeans. The carrier rate is estimated to be 1 in 20 in Southeast Asians, 1 in 30 for Africans, and between 1 in 30 and 1 in 50 for individuals of Mediterranean ancestry. In contrast, for individuals of northern European ancestry, the carrier rate is less than 1 in 1,000.

Genetic testing

A number of different types of genetic abnormalities are associated with alpha-thalassemia. More than one hundred different genetic mutations have been described. Deletion of one or more of the alpha globin chains is the most common genetic defect. This is the type of genetic defect found in approximately 90% of cases.(4) Large genetic rearrangements can also occur from defects in crossover and/or recombination of genetic material during reproduction. Point mutations in one or more of the alpha genes can occur that impair transcription and/or translation of the alpha globin chains.

Testing is commercially available through several genetic labs. The test is most commonly performed by polymerase chain reaction (PCR), which detects genetic deletions associated with thalassemia.(4) Newer testing methods have been developed to facilitate identification of alpha thalassemia mutations, such as multiplex amplification methods and real-time PCR analysis. (5, 6) In patients with suspected alpha-thalassemia and a negative PCR test for genetic deletions, direct sequence analysis of the alpha-globin locus is generally performed to detect point mutations.(4)

Regulatory Status

Genetic testing for alpha thalassemia is available as a laboratory-developed service, subject only to the general laboratory operational regulation under the Clinical Laboratory Improvement Amendments (CLIA) of 1988. Laboratories performing clinical tests must be certified for high-complexity testing under CLIA. The U.S. Food and Drug Administration (FDA) has not regulated these tests to date.


Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.


Genetic testing to confirm a diagnosis of alpha thalassemia is considered not medically necessary.

Genetic testing for alpha thalassemia in other clinical situations is considered experimental, investigational and/or unproven.

NOTE:  Prenatal and preconception testing are addressed in medical policy Prenatal and Preconception Genetic Tests.

Policy Guidelines

Tier 1 molecular pathology CPT code for testing for common deletions or variants:

81257 - HBA1/HBA2 (alpha globin 1 and alpha globin 2)

Tier 2 molecular pathology CPT code, which includes duplication and/or deletion analysis:

81404, including HBA1/HBA2 (alpha globin 1 and alpha globin 2)


This policy was based on a MEDLINE review of the literature through July 15th 2013.

The published literature on genetic testing for alpha thalassemia consists primarily of reports describing the molecular genetics of testing, the types of mutations encountered, and genotype-phenotype correlations. (5-11)

Analytic validity

No published literature was identified on the analytic validity of genetic screening. Some information on the analytic validity of testing was identified from genetic laboratory testing sites. For example, one site reports that “rare” polymorphisms can cause false-negative or false-positive results on gene sequence analysis. (4)

Clinical Validity

No published literature was identified on the clinical validity of genetic screening. Clinical validity is expected to be high when the causative mutation is a large deletion of one or more alpha globin gene, as PCR testing is generally considered highly accurate for this purpose. When a point mutation is present, the clinical validity is less certain.

Clinical Utility

There are several potential areas for clinical utility. Genetic testing can be used to determine the genetic abnormalities underlying a clinical diagnosis of alpha thalassemia. It can also be used define the genetics of alpha globin genes in relatives of patients with a clinical diagnosis of alpha thalassemia. Preconception (carrier) testing can be performed to determine the likelihood of an offspring with an alpha thalassemia syndrome. Prenatal (in utero) testing can also be performed to determine the presence and type of alpha thalassemia of a fetus. Prenatal testing will not be addressed in this policy.

Confirmation of diagnosis. The diagnosis of alpha thalassemia can be made without use of genetic testing. This is first done by analysis of the complete blood count (CBC) and peripheral blood smear, in conjunction with testing for other forms of anemia. Patients with a CBC demonstrating microcytic, hypochromic red blood cell (RBC) indices who are not found to have iron deficiency, have a high likelihood of thalassemia. On peripheral blood smear, the presence of inclusion bodies and target cells is consistent with the diagnosis of alpha thalassemia.

Hemoglobin electrophoresis can distinguish between the asymptomatic carrier states and alpha thalassemia intermedia (HgH disease) by identifying the types and amounts of abnormal hemoglobin present. In the carrier states, >95% of the Hb molecules are normal (HbA) with a small minority of HgBA2 present(1-3%).(2) Alpha thalassemia intermedia is diagnosed by finding a substantial portion of HgbH (1-30%) on electrophoresis.(2) In alpha thalassemia major, the majority of the Hgb is abnormal, in the form of Hgb Bart (85-90%).(2)

However, biochemical testing cannot always reliably distinguish between the asymptomatic carrier state and alpha thalassemia trait. Genetic testing can differentiate between the asymptomatic carrier state (alpha thalassemia minima) and alpha thalassemia trait (alpha thalassemia minor) by elucidating the number of abnormal genes present. This distinction is not important clinically since both the carrier state and alpha thalassemia trait are asymptomatic conditions that do not require medical care. Since the diagnosis of clinically relevant alpha thalassemia conditions can be done without genetic testing, there is little utility to genetic testing of a patient with a clinical diagnosis of thalassemia to determine the underlying genetic abnormalities.


Mutations in the alpha thalassemia gene are common in certain ethnic groups. A variety of alpha thalassemia syndromes can occur, with severity determined by the number of abnormal genes present in an individual. The diagnosis of alpha thalassemia can be made clinically, and the thalassemia syndromes that have clinical implications (HgBH disease, Hg Bart’s) can be diagnosed biochemically without the need for genetic testing. As a result, genetic testing for confirmation of the diagnosis of alpha thalassemia is considered not medically necessary, and is considered experimental, investigational and/or unproven in other clinical situations.


Disclaimer for coding information on Medical Policies

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.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

Refer to the ICD-9-CM Manual.

ICD-10 Codes

Refer to the ICD-10-CM Manual.

Procedural Codes: 81257, 81404
  1. Muncie HL, Jr., Campbell J. Alpha and beta thalassemia. Am Fam Physician 2009; 80(4):339-44.
  2. Galanello R, Cao A. Gene test review. Alpha-thalassemia. Genet Med 2011; 13(2):83-8.
  3. Vichinsky E. Complexity of alpha thalassemia: growing health problem with new approaches to screening, diagnosis, and therapy. Ann N Y Acad Sci 2010; 1202:180-7.
  4. Mayo Medical Laboratories. Alpha-globin gene analysis. 2013. Available online at: Last accessed July 2013.
  5. Fallah MS, Mahdian R, Aleyasin SA et al. Development of a quantitative real-time PCR assay for detection of unknown alpha-globin gene deletions. Blood Cells Mol Dis 2010; 45(1):58-64.
  6. Lacerra G, Musollino G, Di Noce F et al. Genotyping for known Mediterranean alpha-thalassemia point mutations using a multiplex amplification refractory mutation system. Haematologica 2007; 92(2):254-5.
  7. Qadah T, Finlayson J, Newbound C et al. Molecular and cellular characterization of a new alpha-thalassemia mutation (HBA2:c.94A>C) generating an alternative splice site and a premature stop codon. Hemoglobin 2012; 36(3):244-52.
  8. Hellani A, Fadel E, El-Sadadi S et al. Molecular spectrum of alpha-thalassemia mutations in microcytic hypochromic anemia patients from Saudi Arabia. Genet Test Mol Biomarkers 2009; 13(2):219-21.
  9. Joly P, Pegourie B, Courby S et al. Two new alpha-thalassemia point mutations that are undetectable by biochemical techniques. Hemoglobin 2008; 32(4):411-7.
  10. Foglietta E, Bianco I, Maggio A et al. Rapid detection of six common Mediterranean and three non-Mediterranean alpha-thalassemia point mutations by reverse dot blot analysis. Am J Hematol 2003; 74(3):191-5.
  11. Shalmon L, Kirschmann C, Zaizov R. Alpha-thalassemia genes in Israel: deletional and nondeletional mutations in patients of various origins. Hum Hered 1996; 46(1):15-9.
  12. Genetic Testing for Alpha Thalassemia. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (August 2013) Medicine 2.04.104.
April 2014  New medical document. Coverage states: 1) Genetic testing to confirm a diagnosis of alpha thalassemia is considered not medically necessary; 2) Genetic testing for alpha thalassemia in other clinical situations is considered experimental, investigational and/or unproven; 3) NOTE:  Prenatal and preconception testing are addressed in medical policy Prenatal and Preconception Genetic Testing.
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Genetic Testing for Alpha Thalassemia