CAM 204104

Genetic Testing for Alpha- and Beta-Thalassemia

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

Description 
Alpha-thalassemia represents a group of clinical syndromes of varying severity characterized by hemolytic anemia and ineffective hematopoiesis. Genetic defects in any or all of 4 α-globin genes are causative of these syndromes. The rate of mutations in the α-thalassemia gene varies across ethnic groups and is highest in individuals from Southeast Asia, Africa and the Mediterranean region. 

The evidence on genetic testing for the diagnosis of the α-thalassemia syndromes includes case reports and case series that document the association of pathogenic mutations with the clinical syndromes. Relevant outcomes are overall survival, disease-specific survival, test accuracy, test validity, symptoms and quality of life. For the α-thalassemia syndromes that have clinical implications, the diagnosis can be made based on biochemical testing without the need for genetic testing. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome. 

The evidence on genetic testing for patients with hemoglobin H disease to determine prognosis includes cases series that correlate specific mutations with prognosis of disease. Relevant outcomes are overall survival, disease-specific survival, symptoms and quality of life. There is some evidence for a genotypephenotype correlation with disease severity, but there is not currently evidence to indicate that patient management or outcomes would be altered by genetic testing. Therefore, the evidence is insufficient to determine the effects of the technology on health outcomes. 

The evidence for preconception (carrier) genetic testing includes case reports and case series that correlate pathogenic mutations with clinical disease. Relevant outcomes are test accuracy, test validity and changes in reproductive decision making. Preconception carrier testing is intended to avoid the most serious form of α-thalassemia, hemoglobin Bart disease. This condition leads to intrauterine death or death shortly after birth and is associated with increased obstetrical risks for the mother. Screening of populations at risk is first done by biochemical tests, including hemoglobin electrophoresis and complete blood count and peripheral smear, but these tests cannot reliably distinguish between the carrier and trait syndromes and cannot determine which configuration of mutations is present in α-thalassemia trait. They therefore cannot completely determine the risk of a pregnancy with hemoglobin Bart syndrome and hydrops fetalis. Genetic testing can determine with certainty the number of abnormal genes present and, therefore, can more precisely determine the risk of hydrops fetalis. Therefore, the evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

Background 
Hemoglobin, which is the major oxygen-carrying protein molecule of red blood cells, consists of 2 α-globin chains and 2 β-globin chains. Alpha-thalassemia refers to a group of syndromes that arise from deficient production of α-globin chains. Deficient α-globin production leads to an excess of β-globin chains, which results in anemia by a number of mechanisms1

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

The physiologic basis of α-thalassemia is a genetic defect in the genes coding for α-globin production. Each individual carries 4 genes that code for α-globin (2 copies each of HBA1 and HBA2, located on chromosome 16), with the wild genotype (normal) being aa/aa. Genetic mutations may occur in any or all of these 4 α-globin genes. The number of genetic mutations determines the phenotype and severity of the α-thalassemia syndromes. The different syndromes are classified as follows:

  • Silent carrier (α-thalassemia minima). This arises from 1 of 4 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 (α-thalassemia minor). This is also called α-thalassemia trait and arises from the loss of 2 α-globin genes, resulting on 1 of 2 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 in most cases, the Hg electrophoresis is normal.
  • Hemoglobin H disease (α-thalassemia intermedia). This syndrome results from 3 abnormal α-globin genes (a-/--), resulting in a moderate to severe anemia. In HgH disease, there is an imbalance in α- and β-globin gene chain synthesis, resulting in the precipitation of excess β chains into the characteristic hemoglobin H, or β-tetramer. This condition has marked phenotypic variability, but most 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. Inappropriate iron therapy and oxidant drugs should be avoided in patients with HgH disease.

There is an association between genotype and phenotype among patients with HgH disease. Individuals with a nondeletion mutation typically have an earlier presentation, more severe anemia, jaundice and bone changes, and more frequently require transfusions.4

  • Hemoglobin Bart syndrome (α-thalassemia major). This syndrome results from mutations in all 4 α-globin genes (--/--), resulting in absent production of α-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, pre-eclampsia, 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 on 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 α-thalassemia. More than 100 different genetic mutations have been described. Deletion of 1 or more of the α-globin chains is the most common genetic defect. This is the type of genetic defect found in approximately 90% of cases.5 Large genetic rearrangements can also occur from defects in crossover and/or recombination of genetic material during reproduction. Point mutations in 1 or more of the α genes can occur that impair transcription and/or translation of the α-globin chains.

Testing is commercially available through several genetic labs. Targeted mutation analysis for known α-globin gene mutations can be performed by polymerase chain reaction (PCR).4,5 PCR can also be used to identify large deletions or duplications. Newer testing methods have been developed to facilitate identification of α-thalassemia mutations, such as multiplex amplification methods and real-time PCR analysis.6-8 In patients with suspected α-thalassemia and a negative PCR test for genetic deletions, direct sequence analysis of the α-globin locus is generally performed to detect point mutations.5

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.

Policy 

  1. Preconception (carrier) testing for alpha- or beta-thalassemia in prospective parents may be considered MEDICALLY NECESSARY when either parent has evidence of possible alpha-thalassemia (including alpha thalassemia minor, hemoglobin H disease [alpha thalassemia intermedia], or alpha thalassemia major) or beta-thalassemia (including beta thalassemia minor, beta thalassemia intermedia, or beta thalassemia major) based on biochemical testing.    
  2. Genetic testing to confirm a diagnosis of alpha- or beta-thalassemia is MEDICALLY NECESSARY when one of the parents is a known carrier or when other testing to diagnose cause of microcytic anemia has been inconclusive. 
  3. Genetic testing for alpha- or beta-thalassemia in other clinical situations (recognizing that prenatal testing is not addressed in this policy) is INVESTIGATIONAL.

Policy Guidelines
This policy does not address prenatal (in utero or preimplantation) genetic testing for α-thalassemia.

Biochemical testing to determine whether α-thalassemia is present should be the first step in evaluating the presence of the condition. Biochemical testing consists of complete blood count (CBC), microscopic examination of the peripheral smear and Hg electrophoresis. In silent carriers and in α-thalassemia trait, the Hg electrophoresis will most likely be normal. However, there should be evidence of possible α-thalassemia minor on the CBC and peripheral smear. 

The probability of a pregnancy with hemoglobin Bart syndrome (α-thalassemia major) is dependent on the specific genotype found in each parent. Table PG1 summarizes the risk according to each category of α-thalassemia.

Table PG1. Risk of α-Thalassemia

Clinical Diagnosis in Parents

Genotype (parent 1)

Genotype (parent 2)

Probability of HgB Bart syndrome, %

Both parents silent carriers   aa/a-   aa/a-   0%  
One parent silent carrier, one parent trait   aa/a-   a-/a-   0%  
aa/a--   0%  
Both parents trait   aa/--   aa/--   25%  
a-/a-   0%  
a-/a-   aa/--   0%  
a-/a-   0%  
One parent HgH, one parent silent carrier   a-/--   aa/a-   0%  
One parent HgbH, one parent trait   a-/--   aa/--   25%  
a-/a-   0%  
Both parents HgH   a-/--   a-/--   25%  

Hg: hemoglobin.

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 use 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.

Coding
There is a Tier 1 molecular pathology CPT code for testing for common deletions or variants:

81257 - HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g., alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis, for common deletions or variant (e.g., Southeast Asian, Thai, Filipino, Mediterranean, alpha3.7, alpha4.2, alpha20.5 and Constant Spring)

Benefit Application
BlueCard®/National Account Issues
The U.S. Food and Drug Administration (FDA) has not regulated these tests because, to date, they have been offered as laboratory-developed services, 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.

Rationale 
The published literature on genetic testing for α-thalassemia consists primarily of reports describing the molecular genetics of testing, the types of mutations encountered and genotype-phenotype correlations.6,7,9-13 

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.5 

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 1 or more α-globin genes, as polymerase chain reaction (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 α-thalassemia. It can also be used to define the genetics of α-globin genes in relatives of patients with a clinical diagnosis of α-thalassemia. Preconception (carrier) testing can be performed to determine the likelihood of an offspring with an α-thalassemia syndrome. Prenatal (in utero) testing can also be performed to determine the presence and type of α-thalassemia of a fetus. Prenatal testing will not be addressed in this evidence review. 

Confirmation of Diagnosis
The diagnosis of α-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 α-thalassemia.

Hemoglobin electrophoresis can distinguish between the asymptomatic carrier states and α-thalassemia intermedia (HgH disease) by identifying the types and amounts of abnormal hemoglobin present. In the carrier states, greater than 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 HgH (1%-30%) on electrophoresis.2 In α-thalassemia major, the majority of the Hg is abnormal, in the form of hemoglobin Bart (85%-90%).2 

However, biochemical testing, including CBC and hemoglobin electrophoresis, cannot always reliably distinguish between the asymptomatic carrier state and α-thalassemia trait, as the hemoglobin electrophoresis is typically normal in both conditions. Genetic testing can differentiate between the asymptomatic carrier state (α-thalassemia minima) and α-thalassemia trait (α-thalassemia minor) by elucidating the number of abnormal genes present. This distinction is not important clinically because both the carrier state and α-thalassemia trait are asymptomatic conditions that do not require specific medical care treatment. Alpha-thalassemia trait may have overlap in RBC indices values with iron eficiency states, so it is important that iron supplementation not be continued unnecessarily in patients with α-thalassemia trait. However, it would be reasonable to make a diagnosis of α-thalassemia trait in a patient with microcytic, hypochromic RBC indices without evidence of iron deficiency, either before or after a trial of iron supplementation. Because the diagnosis of clinically relevant α-thalassemia conditions can usually be made 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. 

Prognostic Testing in Patients With α-Thalassemia
Among patients with hemoglobin H disease, there is heterogeneity in the nature of the mutation (i.e., deletional vs. nondeletional), with variations across geographic areas and ethnic groups.14 Patients with deletional mutations may have a less severe course of illness than those with nondeletional mutations.14 In a cohort of 147 Thai pediatric patients with HbH disease, those with nondeletional mutations were more likely to have pallor after fever, hepatomegaly, splenomegaly, jaundice, short stature, need for transfusions and gallstones.15 

The evidence suggests that different genetic mutations leading to α-thalassemia are associated with differences in prognosis. New treatments for some of the complications of HbH disease that result from ineffective erythropoiesis and iron overload and may differ for different genotypes are under development.16 However, no evidence was identified to indicate that patient management or outcomes would be changed by prognostic testing. 

Preconception (Carrier) Testing
The major benefit of carrier testing is to define the likelihood of α-thalassemia major. Avoiding a pregnancy with α-thalassemia major is of benefit in that a prospective mother will avoid carrying a nonviable pregnancy, and will avoid the increased obstetrical complications associated with a fetus with α-thalassemia major.

Carrier screening with biochemical testing is recommended for all patients who are from an ethnic group with a high incidence of α-thalassemia. Biochemical screening consists of a CBC with peripheral smear analysis. If there are any abnormalities noted, such as anemia, microcytosis or hypochromia, Hg electrophoresis is then performed to identify the specific types of Hg present and between HgH disease. As noted, the hemoglobin electrophoresis may be normal in the asymptomatic carrier and α-thalassemia trait states, but the states may be suspected based on CBC and peripheral smear analysis. 

Unlike for a clinical diagnosis, for carrier testing, it is important to distinguish between α-thalassemia carrier (1 abnormal gene) and α-thalassemia trait (2 abnormal genes), and also important to distinguish between the 2 variants of α-thalassemia trait, that is the aa/-- (cis variant) and the a-/a- (trans variant). This is because only when both parents have the aa/-- cis variant is there a risk for a fetus with α-thalassemia major.17 When both parents are α -thalassemia carriers (aa/--), there is a 1 in 4 likelihood that an offspring will have α-thalassemia major and hydrops fetalis. These parents may decide to pursue preimplantation genetic diagnosis in conjunction with in vitro fertilization to avoid a pregnancy with hydrops fetalis. 

In this situation, genetic testing has incremental utility over biochemical testing. Whereas biochemical testing can determine whether a silent carrier/trail syndrome is present, and can distinguish those syndromes from HgH disease, it cannot provide a precise determination of the number or pattern of abnormal alpha genes. As a result, using biochemical screening alone, the probability of developing a hemoglobin Bart fetus cannot be accurately assessed. In contrast, genetic testing can delineate the number of abnormal genes with certainty. In addition, genetic testing can determine whether an α-thalassemia trait exists as the cis (aa/--) variant or the trans (a-/a-) variant. Using this information from genetic testing, the probability of hemoglobin Bart syndrome can be determined according to Table 1.

Table 1. Probability of Hemoglobin Bart Syndrome 

Clinical Diagnosis in Parents

Genotype (Parent 1)

Genotype (Parent 2)

Probability of HgB Bart syndrome

Both parents silent carriers   aa/a-   aa/a-   0  
One parent silent carrier, 1 parent trait   aa/a-   a-/a-   0  
aa/a--   0  
Both parents trait   aa/--   aa/--   25  
a-/a-   0  
a-/a-   aa/--   0  
a-/a-   0  
One parent HgH, 1 parent silent carrier   a-/--   aa/a-   0  
One parent HgbH, 1 parent trait   a-/--   aa/--   0
a-/a-   0  
Both parents HgH   a-/--   a-/--   25  

Hg:  hemoglobin.

Parents can also determine the likelihood of HgH disease in an offspring through genetic testing. However, because this is in most cases a mild condition, it is less likely to be considered information that is actionable in terms of altering reproductive decision making.17

Section Summary: Clinical Utility of Genetic Testing
The clinical utility of genetic testing for α-thalassemia may occur in several settings. For confirming a diagnosis of α-thalassemia, because the diagnosis can generally be made on the basis of nongenetic testing, there is little utility to genetic testing. For patients with hemoglobin H disease, there may be a genotype-phenotype correlation for disease severity; however, no studies were identified that suggested that patient management or outcomes would be altered by genetic testing. Therefore, genetic testing for determining the prognosis of hemoglobin H disease is not associated with improved clinical utility. Preconception (carrier) testing is likely to have clinical utility by providing incremental diagnostic information over biochemical testing that can identify the pattern of abnormal alpha genes and estimate more precisely the risk of hydrops fetalis. 

Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in June 2015 did not identify any ongoing or unpublished trials that would likely influence this review.

Summary of Evidence
The evidence on genetic testing for the diagnosis of the αthalassemia syndromes includes case reports and case series that document the association of pathogenic mutations with the clinical syndromes. Relevant outcomes are overall survival, disease-specific survival, test accuracy, test validity, symptoms and quality of life. For the α-thalassemia syndromes that have clinical implications, the diagnosis can be made based on biochemical testing without the need for genetic testing. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome. 

The evidence on genetic testing for patients with hemoglobin H disease to determine prognosis includes cases series that correlate specific mutations with prognosis of disease. Relevant outcomes are overall survival, disease-specific survival, symptoms and quality of life. There is some evidence for a genotype-phenotype correlation with disease severity, but there is not currently evidence to indicate that patient management or outcomes would be altered by genetic testing. Therefore, the evidence is insufficient to determine the effects of the technology on health outcomes. 

The evidence for preconception (carrier) genetic testing includes case reports and case series that correlate pathogenic mutations with clinical disease. Relevant outcomes are test accuracy, test validity and changes in reproductive decision making. Preconception carrier testing is intended to avoid the most serious form of α-thalassemia, hemoglobin Bart disease. This condition leads to intrauterine death or death shortly after birth and is associated with increased obstetrical risks for the mother. Screening of populations at risk is first done by biochemical tests, including hemoglobin electrophoresis and complete blood count and peripheral smear, but these tests cannot reliably distinguish between the carrier and trait syndromes and cannot determine which configuration of mutations is present in α-thalassemia trait. They therefore cannot completely determine the risk of a pregnancy with hemoglobin Bart syndrome and hydrops fetalis. Genetic testing can determine with certainty the number of abnormal genes present and, therefore, can more precisely determine the risk of hydrops fetalis. Therefore, the evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

Practice Guidelines and Position Statements
The Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada published guidelines on carrier testing for thalassemia in 2008.17 These guidelines included the following recommendations:

  • Carrier screening for α-thalassemia should be offered to all woman from ethnic groups with an increased prevalence of α-thalassemia. Initial screening should consist of CBC, Hg electrophoresis (or hemoglobin high performance liquid chromatography), ferritin testing and examination of peripheral smear for the presence of H bodies. 
  • If a woman is found to have abnormal results on initial screen, testing of the partner should be performed using the same battery of tests.

If both partners are found to be carriers of thalassemia, or combination of a thalassemia and hemoglobin variant, they should be referred for genetic counseling. Additional molecular studies may be required to clarify the carrier status of the parents and, thus, the risk to the fetus.

U.S. Preventive Services Task Force Recommendations
Not applicable.

References 

  1. Muncie HL, Jr., Campbell J. Alpha and beta thalassemia. Am Fam Physician. Aug 15 2009;80(4):339-344. PMID 19678601
  2. Galanello R, Cao A. Gene test review. Alpha-thalassemia. Genet Med. Feb 2011;13(2):83-88. PMID 21381239
  3. Vichinsky E. Complexity of alpha thalassemia: growing health problem with new approaches to screening, diagnosis, and therapy. Ann N Y Acad Sci. Aug 2010;1202:180-187. PMID 20712791
  4. Origa R, Moi P, Galanello R, et al. Alpha-Thalassemia. GeneReviews 2005; http://www.ncbi.nlm.nih.gov/books/NBK1435/. Accessed June 17, 2015.
  5. Mayo Medical Laboratories. Alpha-globin gene analysis. 2013; http://www.mayomedicallaboratories.com/testcatalog/Overview/9499. Accessed June 17, 2015.
  6. 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. Jun 15 2010;45(1):58-64. PMID 20363165
  7. 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. Feb 2007;92(2):254-255. PMID 17296579
  8. Grimholt RM, Urdal P, Klingenberg O, et al. Rapid and reliable detection of alpha-globin copy number variations by quantitative real-time PCR. BMC Hematol. 2014;14(1):4. PMID 24456650
  9. 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):244-252. PMID 22524210
  10. 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. Apr 2009;13(2):219-221. PMID 19371220
  11. Joly P, Pegourie B, Courby S, et al. Two new alpha-thalassemia point mutations that are undetectable by biochemical techniques. Hemoglobin. 2008;32(4):411-417. PMID 18654892
  12. 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. Nov 2003;74(3):191-195. PMID 14587048
  13. Shalmon L, Kirschmann C, Zaizov R. Alpha-thalassemia genes in Israel: deletional and nondeletional mutations in patients of various origins. Hum Hered. Jan-Feb 1996;46(1):15-19. PMID 8825457
  14. Fucharoen S, Viprakasit V. Hb H disease: clinical course and disease modifiers. ASH Education Program Book. January 1, 2009 2009;2009(1):26-34.
  15. Laosombat V, Viprakasit V, Chotsampancharoen T, et al. Clinical features and molecular analysis in Thai patients with HbH disease. Ann Hematol. Dec 2009;88(12):1185-1192. PMID 19390853
  16. Musallam KM, Rivella S, Vichinsky E, et al. Non-transfusion-dependent thalassemias. Haematologica. Jun 2013;98(6):833-844. PMID 23729725
  17. Langlois S, Ford JC, Chitayat D, et al. Carrier screening for thalassemia and hemoglobinopathies in Canada. J Obstet Gynaecol Can. Oct 2008;30(10):950-971. PMID 19038079 

Coding Section

Codes Number Description
CPT  81257 HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g., alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis, for common deletions or variant (eg, Southeast Asian, Thai, Filipino, Mediterranean, alpha3.7, alpha4.2, alpha20.5 and Constant Spring)
  81258 (effective 1/1/2018)  HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; known familial variant
  81259 (effective 1/1/2018)  HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; full gene sequence 
  81269 (effective 1/1/2018) HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; duplication/deletion variants 
  S3845  Genetic testing for alpha-thalassemia 
  S3846  Genetic testing for hemoglobin E beta-thalassemia 
ICD-9-CM  Diagnosis          V26.31 Testing of female genetic disease carrier status
  V26.34 Testing of male for genetic disease carrier status
ICD-10-CM (effective 10/01/15) Z31.430 Encounter of female for testing for genetic disease carrier status for procreative management
  Z31.440 Encounter of male for testing for genetic disease carrier status for procreative management
ICD-10-PCS (effective 10/01/15)  

Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.

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 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, updating title and policy to include Beta thalassemia. Also updating coding. 

07/18/2018 

Annual review, no change to policy intent. 

12/7/2017 

Updating policy with 2018 coding. No other changes. 

07/20/2017 

Annual review, rewriting policy verbiage for clarity. No other changes to policy intent. 

04/25/2017 

Interim review to align with Avalon quarterly schedule. Updated category to Laboratory.

11/08/2016 

Interim review to add medical necessity criteria for testing. No other changes. 

04/27/2016 

Annual review, adding: "Genetic testing for patients with hemoglobin H disease (alpha-thalassemia intermedia) to determine prognosis is considered investigational" to policy. No other change to policy intent. Updating background, description, guidelines, rationale and references. 

04/15/2015 

Annual review, no change to policy intent; however, verbiage related to point #2 in policy has been updated for clarity. Preconception (carrier) testing for α-thalassemia in prospective parents may be considered medically necessary.

04/09/2014

New Policy.


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