Alpha Globin (HBA1 and HBA2) Deletion/Duplication

Background Information: Alpha Globin (HBA1 and HBA2) Deletion/Duplication
Characteristics: Alpha thalassemia is caused by decreased or absent synthesis of the hemoglobin alpha-chain resulting in variable clinical presentations. Alpha (+) thalassemia results from mutation of a single alpha2 globin gene (-a/aa) and is clinically asymptomatic (silent carrier). Alpha (0) thalassemia (trait) is caused by mutation of both alpha2 globin genes (-a/-a), or mutations in the alpha1 and alpha2 globin genes on the same chromosome, (--/aa) and results in mild microcytic anemia. Hemoglobin H disease occurs due to mutation of three alpha globin genes (--/-a) and results in hemolysis with Heinz bodies, moderate anemia, and splenomegaly. Hb Bart Hydrops Fetalis Syndrome results when mutations occur in all four alpha globin genes (--/--) and is lethal in the fetal or early neonatal period. Alpha globin gene triplications result in three active alpha globin genes on a single chromosome.
Incidence: Carrier frequency in Mediterranean (1:30-50), Middle Eastern, Southeast Asian (1:20), African, African-American (1:3).
Inheritance: Autosomal recessive.
Cause: Pathogenic mutations in the alpha globin gene cluster.
Clinical Sensitivity: Varies by ethnicity, up to 95 percent.
Methodology: Multiplex ligation-dependent probe amplification (MLPA) of the alpha globin gene cluster (HBZ, HBM, HBA2, HBA1, HBQ1) and its HS-40 regulatory region.
Analytical Sensitivity and Specificity: 99 percent.
Limitations: Diagnostic errors can occur due to rare sequence variations. Specific breakpoints of large deletions/duplications will not be determined; therefore, it may not be possible to distinguish mutations of similar size. This assay does not assess for non-deletional mutations within the coding or regulatory regions of the alpha globin cluster genes. Individuals carrying both a deletion and duplication within the alpha globin gene cluster may appear to have a normal number of alpha globin gene copies. Rare syndromic or acquired forms of alpha thalassemia associated with ATRX mutations will not be detected.

This test was developed and its performance characteristics determined by ARUP Laboratories. It has not been cleared or approved by the US Food and Drug Administration. This test was performed in a CLIA certified laboratory and is intended for clinical purposes.

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