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.
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)
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)
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.
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.
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